HK1120441B - Drugs for treatment of ovarian cancer - Google Patents

Abstract

The present invention provides compositions of matter, kits and methods for their use in the treatment of cancer. In particular, the invention provides compositions and methods for treating cancer in a subject by inhibiting a poly-ADP-ribose polymerase, as well as providing formulations and modes of administering such compositions.

Description

Medicine for treating ovarian cancer

Cross reference to each other

This application is related to and claims priority from U.S. provisional application No. 60/700,446, filed on 7/18/2005, which is incorporated herein by reference in its entirety.

Background

Cancer is a serious threat in modern society. Because of its unique properties, the growth of malignant cancers presents a serious challenge to modern medicine. Their characteristics include uncontrolled cell proliferation leading to unregulated growth of malignant tissue, ability to invade local and even distant tissues, lack of differentiation, lack of detectable symptoms, and most importantly, lack of effective prophylactic and therapeutic measures.

Cancer can occur in any tissue of any organ at any age. The etiology of cancer has not been elucidated, but several mechanisms are associated with malignant cell growth and transformation, such as genetic susceptibility, chromosome breakage disorders, viruses, environmental factors, and immune disorders. Cancer encompasses a wide variety of medical conditions, affecting millions of patients worldwide. Cancer cells can occur in almost any organ and/or tissue of the body. Cancer occurs when cells in a part of the body begin to grow or differentiate uncontrollably. All cancer types begin with uncontrolled growth of abnormal cells.

Cancer types are numerous, including breast, lung, ovarian, bladder, prostate, pancreatic, cervical, and leukemia. The current major therapeutic modalities are surgery, radiation therapy and chemotherapy. Surgery is generally a radical procedure with potentially serious consequences. For example, all methods of treating ovarian cancer can result in infertility. Certain measures to treat cervical and bladder cancer can lead to infertility and/or sexual dysfunction. Surgery to treat pancreatic cancer may partially or completely resect the pancreas and pose a significant risk to the patient. Breast cancer surgery involves, without exception, the excision of part or the entire breast. Certain prostate cancer procedures may carry a risk of urinary incontinence and impotence. Surgery for lung cancer patients often presents severe postoperative pain due to the need to cut ribs to access and remove cancerous lung tissue. In addition, patients with both lung cancer and other pulmonary diseases, such as emphysema or chronic bronchitis, often experience increased dyspnea after surgery.

Radiation therapy has the advantage of killing cancer cells, but it also can damage non-cancerous tissues. Chemotherapy involves the administration of various anti-cancer drugs to patients, but is often associated with side effects.

Over ten million patients are diagnosed with cancer worldwide each year, and this figure is expected to increase to fifteen million new cases each year by 2020. Cancer causes six million deaths worldwide per year, or accounts for 12% of the total deaths. There is therefore a need to find methods for treating cancer. These methods may provide a basis for pharmaceutical compositions useful in the prevention and treatment of cancer in humans and other mammals.

A series of antitumor drugs have been identified. These drugs include nitro and nitroso compounds and their metabolites, which are the subject of U.S. patent No. 5,464,871 entitled "aromatic nitro and nitroso compounds and their metabolites useful as antiviral and antitumor agents" issued on 11/7/1995, 5,670,518 entitled "aromatic nitro and nitroso compounds and their metabolites useful as antiviral and antitumor agents" issued on 9/23/1997, and 6,004,978 entitled "method of treating cancer using aromatic nitro and nitroso compounds and their metabolites issued on 12/21/1999, the disclosures of which are incorporated herein by reference.

Disclosure of Invention

The present invention relates generally to methods of treating neoplastic diseases using aromatic nitrobenzamide compounds and metabolites thereof. More particularly, it relates to the control and inhibition of mammalian tumor growth using the nitro compound 4-iodo-3-nitrobenzamide, or salts, solvates, isomers, tautomers, metabolites, analogs, or prodrugs thereof.

In one aspect, the invention provides a method of treating cancer and cancer-related diseases comprising administering a pharmaceutical composition comprising a compound of formula (Ia) in combination with one or more other pharmacologically active agents. In another aspect, the invention provides a method of treating cancer and cancer-related diseases comprising administering a compound of formula (Ia) in combination with Buthionine Sulfoximine (BSO). The compounds of formula (Ia) can also be used in combination with a benzopyranone compound of formula (II), with or without BSO.

In some preferred embodiments, the cancer is ovarian, endometrial, cervical, pancreatic, bladder, eye, central nervous system, renal, thyroid, and lung cancer. In some preferred embodiments, the cancer is ductal breast cancer, lobular breast infiltrating cancer, ductal breast cancer, mucinous breast cancer, peripheral blood promyelocytic leukemia, ovarian adenocarcinoma that has metastasized the peritoneal cavity, prostate adenocarcinoma, transitional cell carcinoma of the bladder, pancreatic ductal epithelial carcinoma, pancreatic ductal adenocarcinoma, cervical epithelial adenocarcinoma, and lung cancer. In some preferred embodiments, the cancer is lobular breast infiltrative cancer, intraductal breast cancer, and breast mucinous cancer. In some preferred embodiments, the cancer is colon cancer, prostate cancer, liver cancer, leukemia, glioma, and melanoma.

In some preferred embodiments of the above aspects of the invention, the treatment further comprises surgery, radiation therapy, chemotherapy, gene therapy, immunotherapy and combinations thereof. In some preferred embodiments, the compound is administered intravenously. In some preferred embodiments, poly-ADP-ribose polymerase (PARP) molecules are inhibited by the compounds of the present invention. In some preferred embodiments, the subject undergoes apoptosis, cell cycle arrest and/or necrosis of tumor cells following administration of a compound of the invention.

The present invention relates to compositions of matter and pharmaceutical compositions for treating cancer and methods of use. For example, a composition of the invention can be a combination of two or more compounds described herein and/or a combination of two or more forms of a compound described herein. The pharmaceutical composition of the present invention may be a composition suitable for administration to a subject.

Brief Description of Drawings

FIG. 1 shows the effect of nitrobenzamide compounds on BT474 breast cancer cell line with and without cotreatment of Buthionine Sulfoximine (BSO).

FIG. 2 shows the effect of nitrobenzamide and benzopyrone compounds on Ovcar3 and Skov3 ovarian cancer cell lines with or without BSO co-treatment.

FIGS. 3A and 3B show the effect of nitrobenzamide and benzopyrone compounds on lung cancer cell lines with or without BSO co-treatment.

FIG. 4 shows the effect of nitrobenzamide and benzopyrone compounds on lung cancer cell lines with or without BSO co-treatment.

FIG. 5 shows the effect of nitrobenzamide compounds on TUCCSUP bladder cancer cell lines.

FIG. 6 shows the effect of nitrobenzamide and benzopyrone compounds on prostate cancer cell lines with or without BSO co-treatment.

FIG. 7 shows the effect of nitrobenzamide and benzopyrone compounds on prostate cancer cell lines with or without BSO co-treatment.

FIG. 8 shows the effect of nitrobenzamide and benzopyrone compounds on pancreatic cancer cell lines with or without BSO co-treatment.

FIG. 9 shows the effect of nitrobenzamide and benzopyrone compounds on pancreatic cancer cell lines with or without BSO co-treatment.

FIG. 10 shows the effect of nitrobenzamide and benzopyrone compounds on pancreatic cancer cell lines with or without BSO co-treatment.

FIG. 11 shows the effect of nitrobenzamide and benzopyrone compounds on cervical cancer cell lines with or without BSO co-treatment.

FIG. 12 shows the effect of nitrobenzamide and benzopyrone compounds in the presence or absence of BSO co-treatment on an in vivo subcutaneous breast cancer model.

FIG. 13 shows the effect of 4-iodo-3-nitrobenzamide in OVCAR3 (human ovarian adenocarcinoma) xenografted nude mouse model.

FIG. 14 shows the effect on body weight during the evaluation of 4-iodo-3-nitrobenzamide in an OVCAR3 (human ovarian adenocarcinoma) xenografted nude mouse model.

FIG. 15 shows the effect of 6-amino-5-iodo-2H-1-benzopyran-2-one (BP) on breast (MDAMB 231) carcinoma nude mouse xenografts.

FIG. 16 shows the effect of 6-amino-5-iodo-2H-1-benzopyran-2-one (BP) and 4-iodo-3-nitrobenzamide (BA) on breast (MDA MB231) carcinoma nude mouse xenografts.

Detailed Description

Definition of

"nitrobenzamide compound" refers to a compound of formula (Ia), and pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogs, or prodrugs thereof

Wherein R is₁、R₂、R₃、R₄And R₅Independently selected from hydrogen, hydroxyl, amino, nitro, iodine, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₃-C₇) Cycloalkyl and phenyl, wherein R₁、R₂、R₃、R₄And R₅At least two of the five substituents are always hydrogen, at least one of the five substituents is always nitro, and at least one substituent adjacent to the nitro position is always iodo. R₁、R₂、R₃、R₄And R₅It may also be a halogen group such as chlorine, fluorine or bromine.

"surgery" refers to any therapeutic or diagnostic procedure involving the manipulative action of the hand or the application of an instrument to the body of a human or other mammal to achieve a therapeutic, corrective or diagnostic effect.

"radiation therapy" refers to the exposure of a patient to high-energy radiation, including, but not limited to, x-rays, gamma rays, and neutrons. Such treatments include, but are not limited to, external beam radiation therapy (exothermy), internal beam radiation therapy, implant radiation, brachytherapy, total body radiation therapy, and radiation therapy.

"chemotherapy" refers to the administration of one or more anticancer drugs, such as antineoplastic chemotherapeutic drugs, chemopreventive drugs, and/or other agents to a cancer patient by a variety of methods, including intravenous, oral, intramuscular, intra-abdominal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of suppositories. Chemotherapy may be performed preoperatively to allow the large tumor to shrink prior to surgical resection, and after surgery or radiation therapy to prevent the growth of any residual cancer cells in the body.

The term "effective amount" or "pharmaceutically effective amount" refers to a dosage of a drug that is non-toxic yet sufficient to produce the desired biological, therapeutic and/or prophylactic result. The result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of the physiological system. For example, a therapeutically "effective amount" refers to the amount of a nitrobenzamide compound disclosed herein by itself, or a composition comprising a nitrobenzamide compound herein, that is clinically significant in alleviating the disease. An appropriate effective amount in any particular case can be determined by one of ordinary skill in the art using routine experimentation.

By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material does not produce any undesirable biological effects or interact adversely with any of the components contained in the composition upon administration to a subject.

The term "treatment" and its grammatical equivalents as used herein includes obtaining a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or alleviation of the disease being treated. For example, for cancer patients, therapeutic benefit includes eradication or alleviation of the cancer. A therapeutic benefit may also be the eradication or alleviation of one or more of the physiological symptoms associated with the affected condition, such that an improvement in the patient's symptoms is observed despite the fact that the patient may still be suffering from the affected condition. To obtain a prophylactic benefit, the methods of the invention can be applied to or administered to a patient at risk of developing cancer or a patient reporting one or more physiological symptoms of the disease, even though a diagnosis of the condition may not have been made.

Nitrobenzamide compounds

The compounds employed in the present invention are compounds of the general formula (Ia), and pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogues or prodrugs thereof

Wherein R is₁、R₂、R₃、R₄And R₅Independently selected from hydrogen, hydroxyl, amino, nitro, iodine, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₃-C₇) Cycloalkyl and phenyl, wherein R₁、R₂、R₃、R₄And R₅At least two of the five substituents are always hydrogen, at least one of the five substituents is always nitro, and at least one substituent adjacent to the nitro position is always iodo. R₁、R₂、R₃、R₄And R₅It may also be a halogen group such as chlorine, fluorine or bromine.

One preferred compound of formula Ia is:

4-iodo-3-nitrobenzamide (BA)

The present invention provides the use of the above-described nitrobenzamide compounds for the treatment of breast cancer including ductal breast cancer, other forms of leukemia including acute peripheral blood promyelocytic leukemia, ovarian cancer, lung cancer, bladder cancer, prostate cancer, pancreatic cancer, and cervical cancer, as well as other types of cancer described herein (U.S. patent No. 5,464,871, U.S. patent No. 5,670,518, and U.S. patent No. 6,004,978 are incorporated herein by reference in their entirety). The invention also provides the use of the above nitrobenzamide compounds for the treatment of Gleevac (imatinib mesylate) -resistant patient populations. Gleevac is a tyrosine kinase inhibitor.

In some preferred embodiments, the nitrobenzamide compounds of the present invention are used to treat breast cancer, particularly ductal breast cancer, lobular breast infiltrates, intraductal breast cancer, and breast mucinous carcinoma. In some preferred embodiments, the nitrobenzamide compounds of the present invention are used to treat ovarian and endometrial cancers. In a more preferred embodiment, the nitrobenzamide compounds of the present invention are used to treat lung and colon cancer.

In some preferred embodiments, the nitrobenzamide compounds of the present invention are used to treat bladder and prostate cancer. In some preferred embodiments, the nitrobenzamide compounds of the present invention are used to treat liver cancer and pancreatic cancer. In some preferred embodiments, the nitrobenzamide compounds of the present invention are used to treat leukemia, cervical cancer, glioma and melanoma.

In a further preferred embodiment, the nitrobenzamide compounds of the present invention are used to treat cancer derived from stem cells. In breast cancer and other malignancies, a fraction of tumor cells, "cancer stem cells," have the ability to proliferate extensively and tumor metastasize. Alterations in stem cell fate and growth may play a role in tumorigenesis. Epithelial stem cells have a survival time at least comparable to that of an organism and are therefore considered to be susceptible to a variety of genetic factors which accumulate to cause tumor formation. Many cancers, such as skin and colon cancers, occur in tissues that have cells that are constantly replenished throughout their life cycle. However, critical mutations leading to disease may occur during the tissue formation stage when cells divide exponentially.

Stem cell compartments, which have been identified to date to be present in almost every tissue, can be defined as rare cell subsets, with unique self-renewal and persistence characteristics throughout the life of an organism, unlike differentiated cells, which form a tissue entity, but are generally characterized by post-mitotic behavior and short life spans. The fact that cells require multiple mutations to transform into cancer cells suggests that mutations in most tissues may accumulate in stem cells. Since cancer stem cells are self-renewing, it is suggested that they may be derived from normal stem cells that are self-renewing, or from more differentiated cells that have acquired the unique characteristics of stem cells. A tumor can thus also be regarded as a tissue comprising "differentiated" cells and "cancer stem cell" subsets, which contain tumor material, possibly responsible for secondary tumor formation (metastasis). Thus, the nitrobenzamides of the present invention are useful for targeting cancer of stem cell origin.

The present invention discloses the non-clinical pharmacological results of 4-iodo-3-nitrobenzamide (BA) in human tumor and normal primary cells, as well as in mice, rats and dogs. BA inhibits the proliferation of a variety of human tumor cells in vitro, including breast, colon, prostate, cervical, lung, ovarian, melanoma, lymphoma and leukemia. BA was evaluated in vivo in a number of animal models of tumorigenesis. Administration of BA once daily or twice weekly inhibited tumor growth in human ovarian adenocarcinoma xenograft models of nude and SCID mice, and also positively affected the survival of animals dosed once daily or twice weekly.

BA was administered twice weekly for 3 consecutive weeks, followed by a 1-week washout period, as determined by preclinical evaluation of BA efficacy and safety.

Nitrobenzamide compounds have been reported in the literature to be selectively cytotoxic to malignant cancer cells, but not to be effective on non-malignant cancer cells. See Rice et al, proc.natl.acad.sci.usa 89: 7703-7707(1992). In one embodiment, the nitrobenzamide compounds used in the methods of the invention have a more selective toxic effect on tumor cells than on non-tumor cells.

The effect of nitrobenzamide and nitrosobenzamide compounds on tumorigenesis has been reported to be enhanced when BSO is co-administered to cancer cells. See Mendeleyev et al, Biochemical pharmacol.50 (5): 705-714(1995). Buthionine Sulfoximine (BSO) inhibits gamma glutamylcysteine synthetase, a key enzyme in glutathione biosynthesis, the glutathione moiety responsible for cellular resistance to chemotherapy. See Chen et al, Chem Biol interact. apr 24; 111-112: 263-75(1998). The present invention also provides a method of treating cancer comprising administering a nitrobenzamide and/or a benzopyranone compound in combination with BSO.

In addition to BSO, other gamma glutamylcysteine synthetase inhibitors may also be used in combination with nitrobenzamide and/or benzopyrone compounds. Other suitable analogs of BSO include, but are not limited to, prothionine sulfoximine (protithione sulfoximine), methionine sulfoximine, ethionine sulfoximine, methyl-buthionine sulfoximine, gamma-glutamyl-alpha-aminobutyric acid, and gamma-glutamylcysteine.

Benzopyranone compounds

In some embodiments, the benzamide compound is administered in combination with a benzopyrone compound of formula II. The benzopyranone compounds of the general formula II are:

general formula II

Wherein R is₁、R₂、R₃And R₄Independently selected from H, halogen atom, optionally substituted hydroxyl, optionally substituted amino, optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted C₄-C₁₀Heteroaryl and optionally substituted C₃-C₈Cycloalkyl groups, or salts, solvates, isomers, tautomers, metabolites or prodrugs thereof (U.S. patent No. 5,484,951, incorporated herein by reference in its entirety).

In a preferred embodiment, the present invention relates to benzopyrone compounds of the following general formula II

6-amino-5-iodo-benzopyranones

(BP)

Mechanism of action of nitrobenzamide compounds

The anti-cancer properties of the compounds described herein are believed to be achieved by the modulation of poly (ADP-ribose) polymerase, but are not limited to only one mechanism of action. The mechanism of action of drugs is related to their ability to act as ligands for the ribozyme poly (ADP-ribose) polymerase (PARP-1). See Mendeleyev et al, supra, (1995). PARP-1 is expressed in the nucleus, catalyzing beta-Nicotinamide Adenine Dinucleotide (NAD)⁺) Conversion to nicotinamide and poly-ADP-ribose (PAR). The effects of PARP-1 under steady state conditions appear to be limited to DNA transcription and repair. However when cellular stress triggers DNA damage, PARP-1 activity rises dramatically, which appears to be essential for genomic integrity. Shall et al, mut res.jun 30; 460(1): 1-15(2000).

One of the functions of PARP-1 is the synthesis of biopolymer poly (ADP-ribose). Both poly (ADP-ribose) and PARP-1 are involved in DNA damage repair, apoptosis, maintenance of genomic stability and carcinogenesis. See Masutani et al, Genes, Chromosomes, andcam 38: 339-348(2003). PARP-1 plays a role in DNA repair, in particular in Base Excision Repair (BER). BER is a protective mechanism for mammalian cells when single base DNA is fragmented. PARP-1 binds to the ends of DNA fragments with high affinity through its zinc finger domain, thereby acting as a sensor of DNA damage. Gradwohl et al, proc.natl.acad.sci.usa 87: 990-2994 (190); murcia et al, trends biochem Sci 19: 172-176(1994). DNA fragmentation triggers the binding response of PARP-1 to the cleavage site. In turn, PARP-1 has a hundreds of fold increased catalytic activity (see Simonin et al, J Biol Chem 278: 13454-13461(1993)) and begins to convert self-poly ADP ribosylation (Desmorais et al, Biochim Biophys Acta 1078: 179-186 (1991)) and BER proteins such as DNA-PKcs and molecular scaffold protein XRCC-1. See russetti et al, j.biol.chem.jun 5; 273(23): 14461-14467(1998) and Masson et al, Mol Cell biol. Jun; 18(6): 3563-71(1998). BER proteins are rapidly recruited to sites of DNA damage. El-Kaminsy et al, Nucleic Acid Res.31 (19): 5526-5533 (2003); okano et al, Mol Cell biol.23 (11): 3974-3981(2003). PARP-1 then separates from the DNA break site, but remains in the vicinity of the DNA repair event.

Inhibiting the activity of PARP molecules includes decreasing the activity of such molecules. The term "inhibit" and grammatical variations thereof such as "inhibited" does not require a complete reduction in PARP activity. Such reduction is preferably at least about 50%, at least about 75%, at least about 90%, more preferably at least about 95% of the molecular activity in the absence of inhibition, e.g., in the absence of an inhibitor, such as a nitrobenzamide compound of the present invention. Most preferably, the term means that an observable or measurable reduction in activity occurs. In a treatment plan, inhibition is preferably sufficient to produce a therapeutic and/or prophylactic benefit for the disease being treated. The phrase "does not inhibit" and grammatical variations thereof does not require a complete lack of effect on activity. For example, it means that PARP activity is reduced by less than about 20%, less than about 10%, preferably less than about 5% in the presence of an inhibitor, such as a nitrobenzamide compound of the present invention.

Application of benzamide compound

Cancer type

The present invention provides methods of treating a variety of specific cancers or tumors. For example, the cancer types include adrenocortical carcinoma, anal carcinoma, aplastic anemia, bile duct carcinoma, bladder carcinoma, bone metastasis, adult central nervous system brain tumor, childhood central nervous system brain tumor, breast carcinoma, giant lymph node hyperplasia, cervical carcinoma, childhood non-hodgkin's lymphoma, colon and rectal carcinoma, endometrial carcinoma, esophageal carcinoma, ewing's family tumor, eye carcinoma, gall bladder carcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hodgkin's disease, kaposi's sarcoma, kidney carcinoma, laryngeal and hypopharyngeal carcinoma, acute lymphocytic leukemia, acute myelogenous leukemia, childhood leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, liver carcinoma, lung carcinoid tumor, non-hodgkin's lymphoma, male breast carcinoma, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, malignant lymphoma, and malignant melanoma, Nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, gastric cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulval cancer, and waldenstrom's macroglobulinemia.

Thyroid cancer is the most common malignancy of the endocrine system. Thyroid cancer includes differentiated (papillary or follicular) and poorly differentiated (medullary or degenerative) tumors. Vaginal cancer includes squamous cell carcinoma, adenocarcinoma, melanoma, and sarcoma. Testicular cancer is broadly divided into seminoma and non-seminoma types.

Thymomas are thymic epithelial tumors that may or may not be extensively infiltrated by non-tumor lymphocytes. The term thymoma is commonly used to describe tumors that do not exhibit significant epithelial component atypia. A thymic epithelial tumor that exhibits clear cytological atypical and histological features that are no longer thymus-specific is called a thymus carcinoma (also called a type C thymoma).

The methods provided herein can include the administration of benzamide compounds in combination with other therapeutic methods. The choice of therapy that can be used in combination with the compositions of the present invention depends in part on the disease being treated. For example, to treat acute myeloid leukemia, the benzamide compounds of some embodiments of the invention can be used in combination with radiation therapy, monoclonal antibody therapy, chemotherapy, bone marrow transplantation, gene therapy, immunotherapy, and combinations thereof.

Breast cancer

In one aspect, the invention provides a method of treating breast cancer, preferably ductal carcinoma in ductal tissue of the breast.

There are several types of breast cancer that can be treated using the methods provided herein. Lobular carcinoma in situ and ductal carcinoma in situ are breast cancers that occur in the lobules and ducts, respectively, but have not spread to the adipose tissue or other areas of the body surrounding the breast. Invasive (or invasive) lobular and ductal cancers are cancers that occur in the lobules and ducts, respectively, and have spread to the adipose tissue of the breast and/or other parts of the body. Other breast cancers that may benefit from the treatment provided by the present invention are medullary, jelly-like, tubular and inflammatory breast cancers.

The treatment for breast cancer patients is surgery, immunotherapy, radiotherapy, chemotherapy, endocrine therapy or a combination thereof. Partial lumpectomy and mastectomy are two alternative surgical procedures that may be used in breast cancer patients.

Chemotherapy uses antineoplastic drugs to prevent cancer cell proliferation, invasion, metastasis and death of the patient. There are a variety of drugs that can treat breast cancer, including cytotoxic drugs such as doxorubicin, cyclophosphamide, methotrexate, paclitaxel, thiotepa, mitoxantrone, vincristine, or combinations thereof. Endocrine therapy may be an effective treatment in cases where the remaining mammary tissue still remains endocrine sensitive. The drugs used in this therapy include tamoxifen, megestrol acetate, aminoglutethimide, fluoxymesterone, leuprorelin, goserelin and prednisone.

The methods provided herein can provide beneficial effects to breast cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with surgery, radiation therapy, chemotherapy or endocrine therapy.

Ovarian cancer

In another aspect, the invention provides a method of treating ovarian cancer, including epithelial ovarian tumors. Preferably, the present invention provides a method of treating ovarian cancer selected from the group consisting of: intraovarian adenocarcinoma and adenocarcinoma that has metastasized from the ovary to the abdominal cavity. Possible therapeutic measures for ovarian cancer are surgery, immunotherapy, chemotherapy, hormonal therapy, radiation therapy or a combination thereof. Some possible surgical procedures include lumpectomy, unilateral or bilateral ovariectomy, and/or unilateral or bilateral salpingectomy.

Anticancer agents which may be employed include cyclophosphamide, etoposide, hexamethylmelamine and ifosfamide. Hormone therapy with the drug tamoxifen can be used to atrophy ovarian tumors. The radiation therapy may be selected from external beam radiation therapy and/or brachytherapy.

The methods provided herein can provide beneficial effects to ovarian cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with surgery, radiation therapy, chemotherapy, endocrine therapy, or a combination thereof.

Cervical cancer

In another aspect, the invention provides a method of treating cervical cancer, preferably adenocarcinoma of the cervical epithelium. There are two main types of this cancer: squamous cell carcinoma and adenocarcinoma. The former accounts for approximately 80-90% of all cervical cancers, developing where the ectocervix (the portion closest to the vagina) joins the endocervix (the portion closest to the uterus). The latter develops in the mucus-producing glandular cells of the endocervix. Some cervical cancers have both of the above characteristics and are called adenosquamous carcinomas or mixed carcinomas.

The main therapeutic measures for cervical cancer are surgery, immunotherapy, radiotherapy and chemotherapy. Some possible surgical options are cryosurgery, hysterectomy, and radical hysterectomy. Radiation therapy for cervical cancer patients includes external beam radiation therapy or brachytherapy. Anticancer drugs that can be administered as part of chemotherapy to treat cervical cancer include cisplatin, carboplatin, hydroxyurea, irinotecan, bleomycin, vincristine, mitomycin, ifosfamide, fluorouracil, etoposide, methotrexate, and combinations thereof.

The methods provided herein can provide beneficial effects to cervical cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with surgery, radiation therapy, chemotherapy, or a combination thereof.

Prostate cancer

In another aspect, the present invention provides a method of treating prostate cancer, preferably selected from the group consisting of: adenocarcinoma or adenocarcinoma in which bone metastasis has occurred. Prostate cancer occurs in the male prostatic organs that surround the origin of the urethra. The prostate contains several cell types, but 99% of tumors are adenocarcinomas, which occur in seminiferous gland cells.

Some of the therapeutic measures for prostate cancer patients are surgery, immunotherapy, radiotherapy, cryosurgery, hormonal therapy and chemotherapy. Possible surgical procedures for treating prostate cancer include radical post-pubic resection of prostate cancer, radical perineal resection of prostate cancer, and radical laparoscopic resection of prostate cancer. Some radiation therapy options may be external beam radiation therapy, including three-dimensional conformal radiation therapy, intensity modulated radiation therapy, and conformal proton beam radiation therapy. Brachytherapy (seed implantation or interstitial radiotherapy) is also a viable approach to treating prostate cancer. Cryosurgery is another possible method for treating localized prostate cancer cells.

Hormone therapy, also known as androgen deprivation therapy or androgen suppression therapy, can be used to treat prostate cancer. Several methods of this therapy are possible, including orchiectomy, i.e., the removal of the testis that produces 90% androgen. Another approach is to administer luteinizing hormone-releasing hormone (LHRH) analogs to reduce androgen levels. LHRH analogues that may be used include leuprolide, goserelin, triptorelin and histrelin. LHRH antagonists such as abarelix may also be administered.

Another possible therapy is treatment with anti-androgen drugs that block androgen activity in vivo. Such drugs include flutamide, bicalutamide and nilutamide. This therapy is often used in combination with LHRH analogue administration or orchiectomy, which is known as Combined Androgen Blockade (CAB).

Chemotherapy is indicated for the spread of prostate tumors outside the prostate and for cases where hormonal therapy is ineffective. Anticancer agents such as doxorubicin, estramustine, etoposide, mitoxantrone, vinblastine, paclitaxel, docetaxel, carboplatin, and prednisone may be administered to delay prostate cancer growth, alleviate symptoms, and improve quality of life.

The methods provided herein can provide beneficial effects to prostate cancer patients by administration of or using a combination of administration of a nitrobenzamide compound with surgery, radiation therapy, chemotherapy, hormonal therapy, or a combination thereof.

Pancreatic cancer

In another aspect, the present invention provides a method of treating pancreatic cancer, preferably pancreatic cancer selected from the group consisting of: epithelial cancers in pancreatic duct tissue and adenocarcinoma in pancreatic duct.

The most common type of pancreatic cancer is adenocarcinoma, which occurs in the inner layer of the pancreatic duct. Possible therapeutic measures for pancreatic cancer are surgery, immunotherapy, radiotherapy and chemotherapy. Possible surgical treatment options include distal or total pancreatectomy and pancreatectomy (Whipple surgery).

Radiation therapy is also an option for pancreatic cancer patients, particularly external beam radiation therapy, which focuses radiation onto a tumor with an apparatus outside the body. Another option is intra-operative electron beam irradiation performed during surgery.

Chemotherapy can be used to treat pancreatic cancer patients. Suitable anticancer agents include 5-fluorouracil (5-FU), mitomycin, ifosfamide, doxorubicin, streptozocin, chlorouracin, and combinations thereof.

The methods provided herein can provide beneficial effects to patients with pancreatic cancer by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with surgery, radiation therapy or chemotherapy.

Cancer of the bladder

In another aspect, the invention provides a method of treating bladder cancer, preferably transitional cell carcinoma within the bladder. Bladder cancer is bladder epithelial cancer (transitional cell carcinoma) or a tumor in bladder epithelial cells located in the inner layer of the bladder. The remaining bladder cancer types are squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. Several subtypes of bladder epithelial cancer are classified according to whether they are non-invasive or invasive and whether they are papillary or flat. Non-invasive tumors are located in the bladder epithelium, the innermost layer of the bladder, while invasive tumors spread from the bladder epithelium into deeper layers of the major muscle wall of the bladder. Invasive papillary bladder epithelial cancers present as thin finger-like processes that branch into the hollow central portion of the bladder and also grow outward into the bladder wall. Non-invasive papillary urothelial tumors grow towards the center of the bladder. Non-invasive squamous cell carcinoma (also known as carcinoma in situ) is confined to the layer of cells closest to the hollow interior of the bladder, whereas invasive squamous cell carcinoma invades deeper layers of the bladder, particularly the muscle layer.

The bladder cancer can be treated by surgery, radiation therapy, immunotherapy, chemotherapy, or a combination thereof. Some possible surgical options are transurethral resection, cystectomy or radical cystectomy. Radiation therapy for bladder cancer includes external beam radiation therapy and brachytherapy.

Immunotherapy is another method that may be used to treat patients with bladder cancer. The procedure is typically performed within the bladder, with the therapeutic agent delivered directly to the bladder via a catheter. One approach is to administer bacteria, sometimes used for tuberculosis vaccination, directly to the bladder through a catheter using bacillus calmette-guerin (BCG). The body generates an immune response against the bacteria, thereby attacking and killing the cancer cells.

Another approach to immunotherapy is the administration of interferons, glycoproteins that modulate the immune response. Interferon alpha is commonly used in the treatment of bladder cancer.

Anticancer agents that may be used in chemotherapy for the treatment of bladder cancer include thiotepa, methotrexate, vinblastine, doxorubicin, cyclophosphamide, paclitaxel, carboplatin, cisplatin, ifosfamide, gemcitabine, or combinations thereof.

The methods provided herein can provide beneficial effects to patients with bladder cancer by administration of or using a combination of administration of a nitrobenzamide compound with surgery, radiation therapy, immunotherapy, chemotherapy, or a combination thereof.

Acute myelogenous leukemia

In another aspect, the invention provides a method of treating Acute Myeloid Leukemia (AML), preferably peripheral blood acute promyelocytic leukemia. AML originates in the bone marrow but can spread to other parts of the body including lymph nodes, liver, spleen, central nervous system and testes. Acute means that it develops rapidly and becomes fatal if left untreated within a few months. AML is characterized by immature myeloid cells, usually granulocytes or monocytes, which continue to proliferate and accumulate.

Treatment of AML may employ immunotherapy, radiation therapy, chemotherapy, bone marrow or peripheral blood stem cell transplantation, or a combination of the foregoing methods. Radiation therapy, including external beam radiation therapy, may have side effects. Anticancer agents that may be employed in chemotherapy for AML include cytarabine, anthracyclines, anthracenedione, idarubicin, daunorubicin, idarubicin, mitoxantrone, thioguanine, vincristine, prednisone, etoposide, or combinations thereof.

Monoclonal antibody therapy can be used to treat AML patients. Small molecules or radioactive chemicals can be attached to these antibodies prior to administration to a patient to provide a means of killing leukemia cells in vivo. The monoclonal antibody gemtuzumab ozogamicin (gemtuzumab) is capable of binding to CD33 on AML cells and is useful in treating AML patients who are intolerant of existing chemotherapeutic regimens.

Bone marrow or peripheral blood stem cell transplantation can be used to treat AML patients. Allogenic or autologous transplantation is a possible transplantation protocol.

The methods provided herein can provide beneficial effects to leukemia patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with surgery, radiation therapy, chemotherapy or transplantation therapy.

Other types of leukemia that can also be treated using the methods provided herein include, but are not limited to, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, and myeloproliferative disorders.

Lung cancer

In another aspect, the present invention provides a method of treating lung cancer. The most common type of lung cancer is non-small cell lung cancer (NSCLC), which accounts for approximately 80-85% of lung cancer and can be divided into squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma. Small cell lung cancer accounts for 15-20% of lung cancer.

Treatment options for lung cancer include surgery, immunotherapy, radiation therapy, chemotherapy, photodynamic therapy, or a combination of the foregoing. Among the possible surgical options for treating lung cancer are segmental or wedge resection, lobectomy, or total lung resection. The radiotherapy can be external irradiation radiotherapy or brachytherapy.

Some anticancer drugs that may be employed in chemotherapy for the treatment of lung cancer include cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine, gefitinib, ifosfamide, methotrexate, or combinations thereof. Photodynamic therapy (PDT) can be used to treat patients with lung cancer.

The methods provided herein can provide beneficial effects to lung cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with surgery, radiation therapy, chemotherapy, photodynamic therapy or a combination thereof.

Skin cancer

In another aspect, the present invention provides a method of treating skin cancer. There are many types of cancer that originate in the skin. The most common types are basal cell carcinoma and squamous cell carcinoma which belong to non-melanoma skin cancers. Actinic keratosis is a skin disease that can progress to squamous cell carcinoma. Non-melanin skin cancers rarely spread to other parts of the body. Melanoma is the rarest type of skin cancer and is more likely to invade adjacent tissues and spread to other parts of the body. Different types of treatment for patients with non-melanoma and melanoma skin cancers and actinic keratosis include surgery, radiation therapy, chemotherapy and photodynamic therapy. The available surgical options for skin cancer treatment are morse microsurgery, simple resection, electro-desiccation and curettage, cryosurgery, laser surgery. The radiation therapy can be selected from external-beam radiation therapy or brachytherapy. Other types of treatment that are being clinically tested are biotherapy or immunotherapy, chemoimmunotherapy, topical chemotherapy of fluorouracil and photodynamic therapy.

The methods provided herein can provide beneficial effects to skin cancer patients by administration of or using a combination of administration of a nitrobenzamide compound with surgery, radiation therapy, chemotherapy, photodynamic therapy, or a combination thereof.

Eye cancer and retinoblastoma

In another aspect, the present invention provides a method of treating retinoblastoma of the eye. Retinoblastoma is a malignant retinal tumor. Although retinoblastoma can occur at any age, it most commonly occurs in young children, usually before the age of 5 years. Tumors can appear in one or both eyes. Retinoblastoma is usually localized to the eye and does not spread to adjacent tissues or other parts of the body. Treatment options for treating patients and maintaining vision include extirpation (eye extraction), radiation therapy, cryotherapy, photocoagulation, immunotherapy, thermotherapy and chemotherapy. The radiotherapy can be external irradiation radiotherapy or brachytherapy.

The methods provided herein can provide beneficial effects to patients with retinoblastoma of the eye by administration of or using a combination of nitrobenzamide compounds with surgery, radiation therapy, cryotherapy, photocoagulation, thermotherapy and chemotherapy or combinations thereof.

Eye cancer and intraocular melanoma

In another aspect, the present invention provides a method of treating intraocular (ocular) melanoma. Intraocular melanoma is a rare cancer with cancer cells present at a site within the eye called the uvea. The uveal tract of the eye includes the iris, ciliary body, and choroid. Intraocular melanoma occurs most frequently in middle aged people. Methods of treatment of intraocular melanoma include surgery, immunotherapy, radiation therapy and laser therapy. Surgery is the most common treatment for intraocular melanoma. Possible surgical options are iridectomy, trabeculectomy, iridocyclictomy, choroidectomy, extirpation, and orbital content extirpation. The radiation therapy can be selected from external-beam radiation therapy or brachytherapy. Laser therapy is the destruction of tumors by high intensity light beams, either thermal therapy or photocoagulation.

The methods provided herein can provide beneficial effects to patients with intraocular melanoma by administration of or using a combination of nitrobenzamide compounds with surgery, radiation therapy and laser therapy or combinations thereof.

Endometrial cancer

In another aspect, the present invention provides a method of treating endometrial cancer. Endometrial cancer is a cancer that begins in the lining of the uterus-the endometrium. Some examples of uterine and endometrial cancers include, but are not limited to, adenocarcinoma, adenokeratoma, adenosquamous carcinoma, papillary serous adenocarcinoma, clear cell carcinoma, uterine sarcoma, interstitial sarcoma, mixed malignant mesoderm tumors, and leiomyosarcoma.

The methods provided herein can provide beneficial effects to patients with endometrial cancer by administration of or using a nitrobenzamide compound in combination with surgery, radiation therapy, chemotherapy, gene therapy, photodynamic therapy, angiogenesis inhibition therapy, immunotherapy or a combination thereof.

Liver cancer

In another aspect, the invention provides a method of treating primary liver cancer (cancer originating in the liver). Primary liver cancer can occur in adults and children. Different types of treatment may be used for patients with primary liver cancer. Including surgery, immunotherapy, radiotherapy, chemotherapy and transdermal ethanol injection. The types of surgery that can be used are cryosurgery, partial hepatectomy, total hepatectomy, and radiofrequency ablation. The radiotherapy can be selected from external beam radiotherapy, brachytherapy, radiosensitizer or radiolabeled antibody. Other types of treatment include hyperthermia and immunotherapy.

The methods provided by the present invention can provide beneficial effects to patients with liver cancer by administration of or using a combination of administration of a nitrobenzamide compound with surgery, radiation therapy, chemotherapy, transdermal ethanol injection, hyperthermia and immunotherapy, or a combination thereof.

Renal cancer

In another aspect, the invention provides a method of treating renal cancer. Renal cancer (also known as renal cell carcinoma or renal adenocarcinoma) refers to a disease in which malignant cells appear in the lining of the renal tubules. Treatment of renal cancer can be performed by surgery, radiotherapy, chemotherapy, and immunotherapy. Among the possible surgical options for treating kidney cancer are segmental nephrectomy, simple nephrectomy, and radical nephrectomy. The radiation therapy can be selected from external-beam radiation therapy or brachytherapy. Stem cell transplantation can also be used to treat kidney cancer.

The methods provided by the present invention can provide beneficial effects to renal cancer patients by administration of or using a combination of nitrobenzamide compounds with surgery, radiation therapy, chemotherapy, immunotherapy and stem cell transplantation, or a combination thereof.

Thyroid cancer

In another aspect, the present invention provides a method of treating thyroid cancer. Thyroid cancer refers to a disease in which cancer (malignant) cells appear in thyroid tissue. The four major types of thyroid cancer are papillary, follicular, medullary, and degenerative cancers. Treatment of thyroid cancer may be by surgery, immunotherapy, radiation therapy, hormonal therapy and chemotherapy. Surgery is the most common treatment for thyroid cancer. Possible surgical options for treating thyroid cancer are lobectomy, near total thyroidectomy, total thyroidectomy and lymph node resection. Radiation therapy may alternatively be external beam radiation therapy or may require the ingestion of a radioactive iodine-containing liquid. Hormone therapy employs hormones to block the growth of cancer cells. In the treatment of thyroid cancer, hormones may be used to block the body from producing other hormones that may cause cancer cells to grow.

The methods provided herein can provide beneficial effects to patients with thyroid cancer by administration of a nitrobenzamide compound or administration of a nitrobenzamide compound in combination with surgery, radiation therapy, hormonal therapy and chemotherapy, or a combination thereof.

AIDS-related cancer

AIDS-related lymphoma

In another aspect, the present invention provides a method of treating AIDS-related lymphomas. AIDS-related lymphomas are diseases that form malignant cells in the lymphatic system of patients with Acquired Immune Deficiency Syndrome (AIDS). AIDS is caused by the Human Immunodeficiency Virus (HIV), which attacks and weakens the body's immune system. Causing the immune system to fail to fight the infection and disease that afflict the body. HIV patients are at increased risk of developing infections, lymphomas, and other types of cancer. Lymphoma is a cancer that affects the white blood cells of the lymphatic system. Lymphomas are divided into two major groups: hodgkin's lymphoma and non-hodgkin's lymphoma. Both Hodgkin's lymphoma and non-Hodgkin's lymphoma may appear in AIDS patients, but non-Hodgkin's lymphoma is more prevalent. AIDS patients when they have non-Hodgkin's lymphoma are referred to as AIDS-related lymphomas. Non-hodgkin's lymphoma may be indolent (slow growing) or aggressive (fast growing). AIDS-related lymphomas are often aggressive. The three major types of AIDS-related lymphomas are diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, and small anaplastic lymphoma.

Treatment of AIDS-related lymphomas is a combination of lymphoma treatment and AIDS treatment. AIDS patients have a diminished immune system function and treatment may be associated with further impairment. For this reason, the dose administered to treat AIDS-related lymphoma patients will generally be lower than in AIDS-free lymphoma patients. Highly active antiretroviral therapy (HAART) is used to slow the progression of HIV. Drugs are also used to prevent and treat infections that may be more severe. Treatment of AIDS-related lymphomas can be achieved by chemotherapy, immunotherapy, radiation therapy, and high-dose chemotherapy and stem cell transplantation. The radiation therapy can be selected from external-beam radiation therapy or brachytherapy. AIDS-related lymphomas can be treated with monoclonal antibody therapy.

The methods provided herein can provide beneficial effects to patients with AIDS-related lymphomas by administration of or using a combination of nitrobenzamide compounds with chemotherapy, radiation therapy, and high-dose chemotherapy, or a combination thereof.

Kaposi sarcoma

In another aspect, the invention provides a method of treating kaposi's sarcoma. Kaposi's sarcoma is a disease in which cancer cells appear in the subcutaneous tissues or mucous membranes of the inner layers of the mouth, nose and anus. Classic kaposi sarcoma commonly occurs in older men of jewish, italy, or mediterranean descent. This type of kaposi's sarcoma progresses slowly, sometimes for 10 to 15 years. Kaposi's sarcoma may occur in patients taking immunosuppressive agents. Kaposi's sarcoma in acquired immunodeficiency syndrome (AIDS) patients is known as infectious Kaposi's sarcoma. Kaposi's sarcoma in AIDS patients typically spreads more rapidly than other types of Kaposi's sarcoma, often occurring in many parts of the body. Kaposi's sarcoma can be treated by surgery, chemotherapy, radiotherapy, and immunotherapy. External radiation therapy is a common method of treating kaposi's sarcoma. Some possible surgical options for treating kaposi's sarcoma are partial resection, electro-desiccation and curettage, and cryotherapy.

The methods provided by the present invention can provide beneficial effects to Kaposi's sarcoma patients by administration of a nitrobenzamide compound or by administration of a nitrobenzamide compound in combination with surgery, chemotherapy, radiation therapy, and immunotherapy, or a combination thereof.

Virus induced cancer

In another aspect, the invention provides a method of treating a virus-induced cancer. Several common viruses are the clear or possible cause of some specific malignant etiologies. These viruses either often have a latent phase or rarely can become persistent infections. Carcinogenesis may be associated with increased levels of viral activation in infected hosts, manifested by high viral loads or impaired immune control. The major viral-malignant tumor systems include Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and hepatocellular carcinoma; human lymphotropic virus type 1 (HTLV-1) and adult T cell leukemia/lymphoma; and Human Papilloma Virus (HPV) and cervical cancer. Generally, these malignancies occur early in life, often in middle age or earlier.

Virus induced hepatocellular carcinoma

The causal relationship between HBVA and HCV and hepatocellular carcinoma or liver cancer has been determined by actual epidemiological data. They all act by chronic replication in the liver, causing cell death and subsequent regeneration. There are different types of treatment for patients with liver cancer. They include surgery, immunotherapy, radiotherapy, chemotherapy and transdermal ethanol injection. The types of surgery that can be used are cryosurgery, partial hepatectomy, total hepatectomy, and radiofrequency ablation. The radiotherapy can be selected from external beam radiotherapy, brachytherapy, radiosensitizer or radiolabeled antibody. Other types of treatment include hyperthermia and immunotherapy.

The methods provided herein can provide beneficial effects to patients with virally-induced hepatocellular carcinoma by administration of or using a combination of nitrobenzamide compounds with surgery, radiation therapy, chemotherapy, transdermal ethanol injection, hyperthermia and immunotherapy, or a combination thereof.

Virus induced adult T cell leukemia/lymphoma

The association of HTLV-1 with adult T cell leukemia (ATL) has been established. Unlike other oncogenic viruses found worldwide, HTLV-1 is highly regionally restricted, mainly occurring in the southern japan, the caribbean, west and middle africa, and the southern pacific island. Evidence for causal relationships includes the monoclonal integration of the viral genome in the vector in almost all cases of ATL. The risk factors for HTLV-1 associated malignancies are perinatal infections, high viral load and males.

Adult T cell leukemia belongs to cancers of the blood and bone marrow. The standard treatments for adult T cell leukemia/lymphoma are radiation therapy, immunotherapy and chemotherapy. The radiation therapy can be selected from external-beam radiation therapy or brachytherapy. Other methods of treating adult T cell leukemia/lymphoma include immunotherapy and high dose chemotherapy and stem cell transplantation.

The methods provided herein can provide beneficial effects to adult patients with T cell leukemia by administration of or using a combination of nitrobenzamide compounds with radiation therapy, chemotherapy, immunotherapy and high dose chemotherapy with stem cell transplantation, or a combination thereof.

Virus induced cervical cancer

Cervical infection with Human Papillomavirus (HPV) is the most common cause of cervical cancer. Not all women infected with HPV develop cervical cancer. Cervical cancer generally develops slowly. Before the cervix becomes cancerous, cervical cells undergo a change known as dysplasia, and abnormal cells begin to appear in the cervical tissue. Thereafter, the cancer cells begin to grow and spread deeper into and adjacent to the cervix. Standard treatments for cervical cancer are surgery, immunotherapy, radiotherapy and chemotherapy. The types of procedures that can be used are conization, total hysterectomy, bilateral salpingo-oophorectomy, radical hysterectomy, pelvic clearance, cryosurgery, laser surgery, and electroconvulctomy. The radiation therapy can be selected from external-beam radiation therapy or brachytherapy.

The methods provided herein can provide beneficial effects to adult cervical cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with radiation therapy, chemotherapy, or a combination thereof.

Cancer of the central nervous system

Brain and spinal cord tumors refer to abnormal growth of tissue as a major component of the Central Nervous System (CNS) in the skull or vertebral bones. Benign tumors are noncancerous, while malignant tumors are cancerous. The CNS is enclosed in hard bone (i.e. skull and spine) and any abnormal growth, whether benign or malignant, can therefore stress sensitive tissues and affect function. Tumors originating in the brain or spinal cord are referred to as primary tumors. Most primary tumors are caused by uncontrolled growth of cells that surround and support neurons. In a small number of individuals, a primary tumor may result from a particular genetic disorder (e.g., neurofibroma, tuberous sclerosis) or from exposure to radiation or carcinogenic chemicals. The etiology of most primary tumors is not well defined.

The first step in diagnosing brain and spinal tumors is to perform neurological examinations. Special imaging techniques (computed tomography, magnetic resonance imaging, positron emission tomography) may also be employed. Laboratory tests included EEG and lumbar puncture. Tissue biopsy, which is a surgical procedure for taking a tissue sample from a suspected tumor, is helpful to a physician in diagnosing the type of tumor.

Tumors are classified according to the cell types from which they may be derived. The most common adult primary brain tumors originate from astrocytes in the brain, which constitute the blood-brain barrier and supply nutrients to the central nervous system. This type of tumor, known as glioma (astrocytoma, anaplastic astrocytoma or glioblastoma multiforme), accounts for 65% of all central nervous system tumors. Such tumors include, but are not limited to, oligodendroglioma, ependymoma, meningioma, lymphoma, schwannoma, and medulloblastoma.

CNS neuroepithelial tumors

Astrocytic tumors, such as astrocytomas; degenerative (malignant) astrocytomas, such as hemispheric, diencephalon, ocular, brainstem, cerebellar; glioblastoma multiforme; hairy cell astrocytomas, such as hemispheric, diencephalon, ocular, brainstem, cerebellar; giant cell astrocytoma under ependymal membrane; and pleomorphic yellow astrocytomas. Oligodendroglioma tumors, such as oligodendroglioma; and degenerative (malignant) oligodendrogliomas. Ependymal tumors, such as ependymal tumors; degenerative ependymoma; myxopapillary ependymoma; and subintimal neoplasia. Mixed gliomas, such as mixed oligodendroastrocytomas; degenerative (malignant) oligoastrocytoma; and other tumors (e.g., ependymal-astrocytoma). Neuroepithelial tumors of undetermined origin, such as polar glioblastoma; astrocytomas; and brain glioma. Choroid plexus tumors, such as choroid plexus papilloma; and choroid plexus cancer (degenerative choroid plexus papilloma). Neuronal and mixed neuronal-glial cell tumors, such as ganglioneuroma; dysplastic cerebellar ganglion cell tumors (Lhermitte-Duclos); ganglioglioma; anaplastic (malignant) ganglionic gliomas; infant connective tissue proliferative gangliogliomas such as infant connective tissue proliferative astrocytomas; central neuroblastoma; neuroepithelial tumors that are dysplastic for embryos; olfactory neuroblastoma (nasal glioma). Pineal parenchymal tumors, such as pineal cytoma; pineal blastoma; and mixed pinealocytoma/pinealoblastoma. Tumors with a neuroblast or glioblast component (embryonic tumors), such as myeloid epitheliomas; primary neuroectodermal tumors with pluripotent differentiation, such as medulloblastoma; primary neuroectodermal tumors of the brain; neuroblastoma; retinoblastoma; and ependymoblastoma.

Other CNS tumors

Tumors of the saddle area, such as pituitary adenoma; pituitary cancer; and craniopharyngioma. Hematopoietic cell tumors, such as primary malignant lymphoma; a plasmacytoma; and granulocytic sarcoma. Germ cell tumors, such as germ cell tumors, embryonal carcinomas; yolk sac tumors (endodermal sinus tumors); choriocarcinoma; teratoma; and mixed germ cell tumors. Meningeal tumors, such as meningioma; atypical meningiomas; and anaplastic (malignant) meningiomas. Non-meningeal epithelial tumors of the meninges, such as benign stromal tumors; malignant stromal tumors; primary melanocytic injury; hematopoietic cell neoplasms; and tumors of undefined tissue origin, such as hemangioblastoma (hemangioblastoma). Cranial and spinal nerves tumors, such as schwann cell tumors (neuroblastoma, schwannomas); neurofibroma; malignant peripheral nerve sheath tumors (malignant schwann cell tumors), such as epithelioid, diffuse interstitial or epithelial differentiation and melanoma. Local expansion of regional tumors; such as ganglioneuroma (chemoreceptor tumor); chordoma; chondroma; chondrosarcoma; cancer. Metastatic tumors, unclassified tumors and cysts and tumor-like lesions, such as Rathke chapters; an epidermal cyst; a dermoid cyst; a third ventricular jelly cyst; an enterogenic cyst; a glial cyst; granulosa cell tumors (granulomatous tumors, pituitary cytoma); hypothalamic neuronal hamartoma; nasal gliosis ectopy; and plasma cell granuloma.

Useful chemotherapeutic agents include, but are not limited to: alkylating drugs, such as cyclophosphamide, ifosfamide, melphalan, chlorambucil, BCNU, CCNU, dacarbazine, procarbazine, busulfan and thiotepa; antimetabolites, e.g. methotrexate, 5-fluorouracil, cytarabine, gemcitabine (Gemzar)) 6-mercaptopurine, 6-thioguanine, fludarabine and cladribine; anthracyclines, such as daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone; antibiotic drugs, such as bleomycin; camptothecin drugs, such as irinotecan and topotecan; taxanes such as paclitaxel and docetaxel; and platinum drugs such as cisplatin, carboplatin, and oxaliplatin.

The treatment means includes surgery, radiotherapy, immunotherapy, hyperthermia, gene therapy, chemotherapy and radiotherapy combined chemotherapy. Physicians may also administer steroids to reduce swelling within the CNS.

The methods provided herein can provide beneficial effects to adult cervical cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with radiation therapy, chemotherapy, or a combination thereof.

Cancer of the peripheral nervous system

The peripheral nervous system consists of nerves that branch from the brain and spinal cord. These nerves form a communication network that connects the CNS and various parts of the body. The peripheral nervous system is further subdivided into the somatic nervous system and the visceral nervous system. The somatic nervous system is composed of nerves leading to the skin and muscles, involved in conscious activity. The visceral nervous system consists of nerves that connect the CNS with visceral organs such as the heart, stomach and intestines. It mediates non-conscious activities.

Auditory neuroma is a benign fibrous growth originating from the balancing nerve, also called the eighth cranial nerve or the vestibulocochlear nerve. Such tumors are non-malignant, i.e., do not spread or metastasize to other parts of the body. The tumor is located deep within the skull, near the important brain center in the brainstem. If the tumor grows, it affects the surrounding structures related to the vital functions. In most cases, such tumors grow slowly over a period of years.

Malignant Peripheral Nerve Sheath Tumors (MPNST) are malignant tumors corresponding to benign soft tissue tumors such as neurofibromatosis and schwannoma. It is most common deep in soft tissue, usually near the nerve trunk. The most common sites include the sciatic, brachial and sacral plexuses. The most common symptom is pain, often prompting a biopsy. Rare, invasive, lethal orbital tumors usually originate in the sensory trigeminal branch of the adult trigeminal nerve. Malignant PNS tumors affect the brain by spreading along nerves, and most patients die within 5 years after clinical diagnosis. MPNST can be divided into three main categories: epithelial-like, mesenchymal or glandular features. Some MPNSTs include, but are not limited to: subcutaneous malignant epithelial schwann cell tumor accompanied by cartilage differentiation, malignant adenoid schwann cell tumor accompanied by perineurium differentiation, malignant peripheral nerve sheath tumor, skin epithelial malignant nerve sheath tumor with rod-like characteristic, epidermal epithelial MPNST, newt tumor (MPNST accompanied by rhabdomyoblast differentiation), and schwann cell tumor accompanied by rhabdomyoblast differentiation. Rare cases of MPNST include multiple sarcoma histotypes, particularly osteosarcoma, chondrosarcoma, and angiosarcoma. They are sometimes difficult to distinguish from malignant mesenchymal tumors of soft tissue.

Other types of PNS cancers include, but are not limited to, malignant fibrocytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mullerian mixed tumor.

The treatment means includes surgery, radiotherapy, immunotherapy, chemotherapy and radiotherapy combined chemotherapy.

The methods provided herein can provide beneficial effects to patients with PNS cancer by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with radiation therapy, chemotherapy, or a combination thereof.

Oral and oropharyngeal cancer

Treatment of patients with Central Nervous System (CNS) cancers remains a difficult task. Cancers such as carcinomas of the cause, larynx, nasopharynx, oropharynx, etc. have been treated with surgery, immunotherapy, chemotherapy, and radiotherapy in combination with chemotherapy. The two commonly used topoisomerase II inhibiting anticancer drugs etoposide and actinomycin D do not cross the blood brain barrier at the doses available.

The methods provided herein can provide beneficial effects to patients with oral and oropharyngeal cancer by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with radiation therapy, chemotherapy, or a combination thereof.

Stomach cancer

Gastric cancer is the result of changes in cells in the lining of the stomach. There are three main types of gastric cancer: lymphoma, gastric stromal tumors, and carcinoid tumors. Lymphoma, a cancer of the immune system tissue, can sometimes occur in the stomach wall. The gastric stromal tumor develops from the stomach wall tissue. Carcinoid tumors are tumors of hormone-producing cells of the stomach.

The etiology of gastric cancer is still controversial. A combination of genetic and environmental (diet, smoking, etc.) factors are thought to play a role. Common treatment methods include surgery, immunotherapy, chemotherapy, radiation therapy, chemotherapy in combination with radiation therapy or biological therapy.

The methods provided herein can provide beneficial effects to gastric cancer patients by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with radiation therapy, chemotherapy, or a combination thereof.

Cancer of testis

Testicular cancer is cancer that commonly occurs in unilateral or bilateral testicles of young men. Testicular cancer occurs in specific cells called germ cells. The two major types of Germ Cell Tumors (GCT) that occur in men are seminomas (60%) and non-seminomas (40%). Tumors may also occur in the supporting and hormone-producing tissues or interstitium of the testis. Such tumors are known as gonadal stromal tumors. The two major types are leydig cell tumors and seltory cell tumors. Secondary testicular tumors refer to tumors that originate in other organs and then spread to the testis. Lymphoma is the most common secondary cancer of the testis.

Conventional treatment methods include surgery, immunotherapy, chemotherapy, radiation therapy, chemotherapy in combination with radiation therapy or biological therapy. Several drugs are commonly used for testicular cancer treatment: platinol (cisplatin), vaseline or VP-16 (etoposide) and blenoxane (bleomycin sulfate). In addition, Ifex (ifosfamide), Velban (vinblastine sulfate) and the like can also be used.

The methods provided herein can provide beneficial effects to patients with testicular cancer by administering or using a combination of administration of a nitrobenzamide compound with radiation therapy, chemotherapy, or a combination thereof.

Thymus gland cancer

The thymus is a small organ located on/in the anterior chest cavity, extending from the base of the larynx to the front of the heart. The thymus contains two major cell types: thymic epithelial cells and lymphocytes. Thymic epithelial cells are the primary cells of thymoma and thymus carcinoma. Lymphocytes in the thymus or lymph nodes can become malignant and develop into cancers known as hodgkin's disease and non-hodgkin's lymphoma. The thymus also contains another, less common cell type, called Kulchitsky cells, or neuroendocrine cells that normally release certain hormones. Such cells may develop into cancers known as carcinoid or carcinoid tumors, which typically release the same type of hormone, similar to other tumors derived from neuroendocrine cells elsewhere in the body.

Conventional treatment methods include surgery, immunotherapy, chemotherapy, radiation therapy, chemotherapy in combination with radiation therapy or biological therapy. Among the anticancer agents that have been used to treat thymoma and thymus cancer are doxorubicin (adriamycin), cisplatin, ifosfamide, and corticosteroids (prednisone). These drugs are often used in combination to improve effectiveness. The drug combination for treating the thymus cancer comprises the combination of cisplatin, doxorubicin, etoposide and cyclophosphamide, and the combination of cisplatin, doxorubicin, cyclophosphamide and vincristine.

The methods provided herein may provide beneficial effects to patients with thymus cancer by administration of a nitrobenzamide compound or by a combination of nitrobenzamide compound administration with radiation therapy, chemotherapy, or a combination thereof.

Combination therapy

In one aspect, the invention provides methods for treating cancer using a combination of different treatment regimens. For example, such combinations include, but are not limited to, one or more nitrobenzamide compounds in combination with one or more different anti-tumor chemotherapeutic, chemopreventive, and/or side-effect limiting agents.

Antitumor chemotherapeutic

Suitable anti-tumor chemotherapeutic agents for use in the present invention include, but are not limited to, alkylating agents, antimetabolites, natural antineoplastic agents, hormonal antineoplastic agents, angiogenesis inhibitors, differentiating agents, RNA inhibitors, antibodies or immunotherapeutic agents, gene therapy agents, small molecule enzyme inhibitors, biological response modifiers, and anti-metastatic agents.

Alkylated drugs

It is known that alkylating drugs act by alkylating macromolecules such as cancer cell DNA, usually strongly electrophilic substances. This activity can disrupt DNA synthesis and cell division. Examples of alkylating agents suitable for use herein include nitrogen mustard and its analogs and derivatives, including cyclophosphamide, ifosfamide, chlorambucil, estramustine, mechlorethamine hydrochloride, melphalan, and uracil mustard. Examples of other alkylating agents include alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, and streptozocin), triazenes (e.g., dacarbazine and temozolomide), ethyleneimine/methylmelamines (e.g., altretamine and thiotepa), and methylhydrazine derivatives (e.g., procarbazine). The class of alkylating drugs also includes alkylating platinum-containing drugs, including carboplatin, cisplatin, and oxaliplatin.

Antimetabolites

Antimetabolic antitumor agents are structurally similar to natural metabolites and can participate in normal metabolic processes of cancer cells, such as nucleic acid and protein synthesis. They are sufficiently different from natural metabolites to interfere with the metabolic processes of cancer cells. Suitable antimetabolic antineoplastic agents for use in the present invention may be classified according to their metabolic processes of influence, including but not limited to folic acid, pyrimidine, purine and cytidine analogs and derivatives. Members of the folate family of drugs suitable for use herein include, but are not limited to, methotrexate (amkson), pemetrexed, and their analogs and derivatives. Pyrimidines suitable for use herein include, but are not limited to, cytarabine, floxuridine, fluorouracil (5-fluorouracil), capecitabine, gemcitabine, and analogs and derivatives thereof. Purine drugs suitable for use herein include, but are not limited to, mercaptopurine (6-mercaptopurine), pentostatin, thioguanine, cladribine, and analogs and derivatives thereof. Cytidine-based drugs suitable for use herein include, but are not limited to, cytarabine (cytosine arabinoside), azacitidine (5-azacytidine), and analogs and derivatives thereof.

Natural antineoplastic medicine

Natural antineoplastic agents include antimitotic drugs, antibiotic antineoplastic agents, camptothecin analogs, and enzymes. Antimitotic drugs suitable for use herein include, but are not limited to, vinca alkaloids such as vinblastine, vincristine, vindesine, vinorelbine, and analogs and derivatives thereof. The drug is derived from the Magasus latus plant, is usually cell cycle specific for the M phase, and binds to tubulin in the microtubules of cancer cells. Other antimitotic drugs suitable for use herein are podophyllotoxins including, but not limited to, etoposide, teniposide, and their analogs and derivatives. Such drugs are primarily directed to the late G2 and S phases of the cell cycle.

The natural antitumor drugs also include antibiotic antitumor drugs. Antibiotic antineoplastic agents are antimicrobial agents with antineoplastic properties that generally interact with cancer cell DNA. Antibiotic antineoplastic agents suitable for use herein include, but are not limited to, bleomycin, dactinomycin, doxorubicin, idarubicin, epirubicin, mitomycin, mitoxantrone, pentostatin, plicamycin, and analogs and derivatives thereof.

The natural antineoplastic classes also include camptothecin analogs and derivatives, which are suitable for use in the present invention, including camptothecin, topotecan, and irinotecan. Such drugs act primarily by targeting the ribozyme topoisomerase I. Another subclass of natural antineoplastic agents is the enzyme, L-asparaginase and variants thereof. L-asparaginase acts by catalyzing the hydrolysis of circulating asparagine to aspartic acid and ammonia, removing L-asparagine in certain cancer cells.

Hormone antineoplastic agent

Hormonal antineoplastics act primarily on hormone-dependent cancer cells associated with prostate tissue, breast tissue, endometrial tissue, ovarian tissue, lymphomas, and leukemias. These tissues may respond to and rely on classes of drugs such as glucocorticoids, progestins, estrogens, and androgens. Both analogues and derivatives which are agonists or antagonists are suitable for use in the present invention for the treatment of tumours. Examples of glucocorticoid agonists/antagonists suitable for use herein are dexamethasone, hydrocortisone, corticosterone, prednisone, mifepristone (RU486), their analogs and derivatives. Progesterone agonist/antagonist subclasses suitable for use herein include, but are not limited to, hydroxyprogesterone, medroxyprogesterone, megestrol acetate, mifepristone (RU486), ZK98299, analogs and derivatives thereof. Examples of estrogen agonist/antagonist subclasses of drugs suitable for use herein include, but are not limited to, estrogen, tamoxifen, toremifene, RU58668, SR16234, ZD164384, ZK191703, fulvestrant, their analogs and derivatives. Examples of aromatase inhibitors that inhibit estrogen production suitable for use herein include, but are not limited to, androstenedione, formestane, exemestane, aminoglutethimide, anastrozole, letrozole, their analogs and derivatives. Examples of androgen agonist/antagonist subclasses of drugs suitable for use herein include, but are not limited to, testosterone, dihydrotestosterone, fluoxymesterone, testolactone, testosterone enanthate, testosterone propionate, gonadotropin releasing hormone agonists/antagonists (e.g., leuprolide, goserelin, triptorelin, buserelin), diethylstilbestrol, abarelix, cyproterone, flutamide, nilutamide, bicalutamide, analogs and derivatives thereof.

Angiogenesis inhibitors

Angiogenesis inhibitors act by inhibiting angiogenesis in tumors. Angiogenesis inhibitors include a wide variety of drugs, including small molecule drugs, antibody drugs, and drugs directed against RNA function. Examples of angiogenesis inhibitors suitable for use herein include, but are not limited to, ranibizumab (ranibizumab), bevacizumab, SU11248, PTK787, ZK222584, CEP-7055, angiozyme, dalteparin, thalidomide, suramin, CC-5013, combretastatin a4 phosphate, LY317615, soy isoflavones, AE-941, interferon alpha, PTK787/ZK222584, ZD6474, EMD 121974, ZD6474, BAY 543 9006, celecoxib, halofuginone hydrobromide, bevacizumab, analogs, variants or derivatives thereof.

Differentiation-promoting agents

Differentiation-promoting agents inhibit tumor growth by inducing the mechanism of cancer cell differentiation. A subclass of such agents suitable for use herein include, but are not limited to, vitamin a analogs or retinoids, and peroxisome proliferator-activated receptor agonists (PPARs). Retinoids suitable for use herein include, but are not limited to, vitamin a aldehyde (retinal), retinoic acid, fenretinide, 9-cis-retinoic acid, 13-trans-retinoic acid, all-trans retinoic acid, isotretinoin, tretinoin, retinyl palmitate, analogs and derivatives thereof. PPAR agonists suitable for use herein include, but are not limited to, troglitazone, ciglitazone, tesaglitazar, their analogs and derivatives.

RNA inhibitors

Certain RNA inhibitors are useful for inhibiting the expression or translation of messenger RNA ("mRNA") associated with a cancer phenotype. Examples of such agents suitable for use herein include, but are not limited to, short interfering RNA ("siRNA"), ribozymes, and antisense oligonucleotides. Specific examples of RNA inhibitors suitable for use herein include, but are not limited to, Cand5, Sirna-027, Fumivir, and angiozyme.

Antibody/immunotherapeutic agent

The antibody drug can bind to a target selectively expressed in the cancer cell, thereby killing cells associated with the target with the complex or causing an immune response in the body to destroy the cancer cell. Immunotherapeutic drugs include polyclonal or monoclonal antibodies. Antibodies include non-human animal (e.g., mouse) and human components, or include fully human components ("humanized antibodies"). Examples of monoclonal immunotherapeutic drugs suitable for use herein include, but are not limited to, rituximab, tositumomab, ibritumomab tiuxetan, which target the CD-20 protein. Other examples suitable for use herein include trastuzumab, epirubizumab, bevacizumab, cetuximab, carcinoembryonic antigen antibodies, gemtuzumab, alemtuzumab, mapatumumab, panitumumab (panitumumab), EMD 72000, TheraCIM hR3, 2C4, HGS-TR2J, and HGS-ETR 2.

Gene therapy medicine

Gene therapy drugs insert copies of a gene into a specific set of patient cells and can target both cancerous and non-cancerous cells. The goal of gene therapy is to replace the altered gene with a functional gene, stimulate the patient's immune response to cancer, make cancer cells more susceptible to chemotherapy, place a "suicide" gene in cancer cells, or inhibit angiogenesis. The gene may be delivered to the target cell by a virus, liposome, or other vehicle or vector. This can be achieved as follows: the gene-vector composition is injected directly into the patient, or ex vivo after infecting the cells. These compositions are suitable for use in the present invention.

Small molecule enzyme inhibitors

Some small molecule therapeutic agents are capable of targeting tyrosine kinase enzyme activity or downstream signaling signals of certain cellular receptors such as epidermal growth factor receptor ("EGFR") or vascular endothelial growth factor receptor ("VEGFR"). Such targeting of small molecule therapeutics can play an anticancer role. Examples of such agents suitable for use herein include, but are not limited to, imatinib, gefitinib, erlotinib, lapatinib (lapatinib), canertinib (canertinib), ZD6474, sorafenib (BAY 43-9006), ERB-569, and analogs and derivatives thereof.

Biological response regulating medicine

Some protein or small molecule drugs can be used in anticancer therapy, which act through direct antitumor or indirect effects. Examples of direct acting drugs suitable for use herein include, but are not limited to, differentiating agents such as retinoids and retinoic acid derivatives. Indirect-acting drugs suitable for use herein include, but are not limited to, drugs that modulate or enhance immunity or other systems such as interferons, interleukins, hematopoietic growth factors (e.g., erythropoietin), and antibodies (monoclonal and polyclonal).

Anti-metastatic drug

The process by which cancer cells spread from the primary tumor site to other parts of the body is called cancer metastasis. Some drugs have anti-metastatic properties and can be used to inhibit cancer cell spreading. Examples of such agents suitable for use herein include, but are not limited to, marimastat, bevacizumab, trastuzumab, rituximab, erlotinib, MMI-166, GRN163L, capture-killer peptide (hunter-killer peptide), Tissue Inhibitor of Metalloproteinases (TIMP), analogs, derivatives and variants thereof.

Chemopreventive agent

Some drugs can be used to prevent the initial onset of cancer, or to prevent recurrence or metastasis. Such chemopreventive agents can be used in combination with one or more other anti-cancer agents, including nitrobenzamide compounds, to treat and prevent the recurrence of cancer. Examples of chemopreventive agents suitable for use herein include, but are not limited to, tamoxifen, raloxifene, tibolone, bisphosphonates, ibandronate, estrogen receptor modulators, aromatase inhibitors (letrozole, anastrozole), luteinizing hormone releasing hormone agonists, goserelin, vitamin A, retinal, retinoic acid, fenretinide, 9-cis-retinoic acid, 13-cis-retinoic acid, all-trans retinoic acid, isotretinoin, tretinoin, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, celecoxib, polyphenols, polyphenol E, green tea extract, folic acid, glucaric acid, interferon alpha, anetholethione, zinc, pyridoxine, finasteride, doxazosin, and, Selenium, indole-3-methanol, alpha-difluoromethylornithine, carotenoids, beta-carotene, lycopene, antioxidants, coenzyme Q10, flavonoids, quercetin, curcumin, catechin, epigallocatechin gallate, N-acetylcysteine, indole-3-methanol, inositol hexaphosphate, isoflavones, gluconic acid, rosemary, soy, sabal and calcium. Another example of a chemopreventive agent suitable for use in the present invention is a cancer vaccine. This can be generated by immunizing the patient with all or part of the cancer cell types targeted by the vaccination program.

Side effect-limiting drugs

When the nitrobenzamide compound is used alone or in combination with other antitumor compounds for treating cancer, drugs capable of alleviating the side effects produced by antitumor drugs can be administered simultaneously. Such drugs suitable for use herein include, but are not limited to, antiemetics, anti-mucositis drugs, pain control drugs, infection control drugs, and anti-anemic/anti-thrombocytopenic drugs. Examples of antiemetics suitable for use herein include, but are not limited to, 5-hydroxytryptamine 3 receptor antagonists, metoclopramide, steroids, lorazepam, ondansetron, cannabinols, analogs and derivatives thereof. Examples of anti-mucositis agents suitable for use herein include, but are not limited to, palifermin (keratinocyte growth factor), glucagon-like peptide 2, teduglutide (teduglutide), L-glutamine, amifostine, and fibroblast growth factor 20. Examples of pain management drugs suitable for use herein include, but are not limited to, opioids, opiates, and non-steroidal anti-inflammatory compounds. Examples of drugs suitable for use herein for controlling infection include, but are not limited to, antibacterial drugs such as aminoglycosides, penicillins, cephalosporins, tetracyclines, clindamycin, lincomycin, macrolides, vancomycin, carbapenems, monobactams, fluoroquinolones, sulfonamides, furantoins, their analogs and derivatives. Examples of drugs suitable for use herein that can treat chemotherapy-related anemia or thrombocytopenia include, but are not limited to, erythropoietin and thrombopoietin.

There are several additional therapies that are suitable for use in combination with the nitrobenzamide compounds described herein and other compounds. See, for example, Goodman and Gilman, the pharmacological Basis of Therapeutics 11th ed. Brunton LL, Lazo JS, and Parker KL, ed. McGraw-Hill, New York, 2006.

Formulation, route of administration and effective dose

Another aspect of the invention relates to formulations and routes of administration of pharmaceutical compositions comprising the nitrobenzamide compounds. These pharmaceutical compositions are useful for treating cancer in accordance with the methods detailed above.

The compounds of formula Ia may be provided as prodrugs and/or may be allowed to interconvert in vivo into the nitrosobenzamide form following administration. Thus, the nitrobenzamide forms and/or nitrosobenzamide forms, or pharmaceutically acceptable salts, can be used to develop formulations for use in the present invention. Also, in some embodiments, the compound may be used in combination with one or more other compounds, or in one or more other forms. For example, a formulation may contain a nitrobenzamide compound and its acid form in a particular ratio determined by the relative potency of the respective forms and the intended indication. The two forms may be co-formulated in the same dosage unit, e.g., in one part of a cream, suppository, tablet, capsule or sachet to be dissolved in a beverage; or each form may be formulated separately in separate units, such as two parts of a cream, two parts of a suppository, two parts of a tablet, two parts of a capsule, one part of a tablet with one part of a liquid that dissolves the tablet, one part of a powder packet with one part of a liquid that dissolves the powder, and so forth.

Compositions comprising a combination of a nitrobenzamide compound and another active agent are effective. The two compounds and/or the two forms of one compound can be co-formulated in the same dosage unit, e.g., in one cream, suppository, tablet, capsule or sachet to be dissolved in a beverage; or each form may be formulated separately in separate units, such as two parts of a cream, a suppository, a tablet, two parts of a capsule, one part of a tablet with one part of a liquid that dissolves the tablet, one part of a powder packet with one part of a liquid that dissolves the powder, and so forth.

The term "pharmaceutically acceptable salt" refers to salts used in the present invention that retain the biological effectiveness and properties of the compound and are biologically or otherwise desirable. For example, pharmaceutically acceptable salts do not interfere with the beneficial effects of the compounds of the present invention in the treatment of cancer.

Typical salts are inorganic ionic salts such as sodium, potassium, calcium and magnesium ions. These salts include salts of inorganic or organic acids, such as hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, lactic, mandelic, malic, citric, tartaric, or maleic acid. In addition, if the compounds used in the present invention contain a carboxyl group or other acidic group, they can be converted into pharmaceutically acceptable addition salts using inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

For oral administration, the active compound can be combined with pharmaceutically acceptable carriers well known in the art to formulate the compound easily. Such carriers enable the compounds of the invention to be formulated as tablets (including chewable tablets), pills, troches, capsules, lozenges, hard candies, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and the like, for oral ingestion by a patient to be treated. The formulation may contain a pharmaceutically acceptable carrier, including solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Typically, a compound of the present invention is included at a concentration level of from about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80%, or about 90% by weight of the total oral dosage form composition in an amount sufficient to provide the desired dosage unit.

Aqueous suspensions may contain the nitrobenzamide compound in association with pharmaceutically acceptable excipients such as suspending agents (e.g. methylcellulose), wetting agents (e.g. lecithin, lysolecithin and/or long chain fatty alcohols), as well as colouring agents, preservatives, flavouring agents and the like.

In some embodiments, the compounds may need to be made into solutions using oils or non-aqueous solvents due to, for example, the presence of large lipophilic moieties. Alternatively, emulsions, suspensions or other formulations, such as liposomal formulations, may be used. For liposome formulations, any known method of preparing liposomes for the treatment of disease can be used. See, e.g., Bangham et al, j.mol.biol, 23: 238-: 4149 4198(1978), incorporated herein by reference. Ligands may also be attached to the liposomes to direct the composition to a particular site of action. The compounds of the invention may also be added to food products such as cream cheese, butter, salad dressings or ice cream to facilitate dissolution, administration and/or compliance by certain patient groups.

Pharmaceutical preparations for oral use can be obtained using solid excipients, optionally after adding suitable auxiliaries (if desired), grinding the resulting mixture and processing the mixture of granules to give tablets or dragee cores. Suitable excipients include, inter alia: fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; flavoring ingredients, cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. The compounds may also be formulated as sustained release formulations.

Dragee cores can be suitably coated. For this purpose, concentrated sugar solutions may be employed, optionally containing gum arabic, talc, polyvinyl pyrrolidone, carbopol gum, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to distinguish between different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in admixture with fillers, for example lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All oral formulations should be in dosages suitable for administration.

For injection, the inhibitors of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution or physiological saline. The composition may further comprise one or more excipients, such as preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, and the like. Formulation methods are well known in the art, for example, as disclosed in mack publishing co, latest version of Remington's Pharmaceutical Sciences published by Easton P. The compounds may also be formulated for transmucosal, buccal, inhalation, parenteral, transdermal, and rectal administration.

In addition to the above formulations, the compounds may also be formulated as depot (depot) formulations. Such long acting formulations may be administered by implantation or transdermal delivery (e.g. subcutaneous or intramuscular), intramuscular injection or using a transdermal patch. For example, the compounds may be formulated with suitable polymers or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins, or sparingly soluble derivatives such as a sparingly soluble salt.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein: wherein the active ingredient is present in an effective amount, i.e., an amount effective to obtain a therapeutic and/or prophylactic benefit in at least one cancer described herein. The actual effective amount for a particular application depends on the following factors: the disease to be treated, the condition of the subject, the formulation and route of administration, and other factors well known to those skilled in the art. Effective amounts of nitrobenzamide compounds can be readily determined by one skilled in the art in light of the present disclosure, and can be determined using routine optimization techniques.

Examples

Example 1

In vitro assay-cytotoxicity assay

Different types of cancer cell lines or primary cells from different sources were seeded in 48-well plates (5X 10)⁴) Or 96-well plates (2X 10)⁴) In (1). The cells are cultured in a suitable medium. The culture was placed at 37 ℃ and filled with 95% O₂/5％CO₂A humid air incubator. After cell inoculation (24 hours), the medium was removed and culture was continued with medium containing different concentrations of INO2BA or INH2BP with or without 200 μ M BSO. After 6 days of incubation at 37 ℃ Cell Viability was determined using Cell Titer-Blue, Cell Viability Assay (Promega). (see O' Brien, J. et al (2000) Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of macromolecular cell oxidation. Eur. J. biochem.267, 5421-26 and Gonzalez, R.K. and Tarloff, J.B. (2001) Evaluation of genetic tissue activities for Alamar Blue and MTT reduction). The detection method introduces a fluorescent colorimetric/colorimetric growth indicator, and the principle of the detection method is based on the reduction of a vital dye. Cytotoxicity was determined by growth inhibition.

Cytotoxicity was also detected using viable cell counts. The cells were harvested by washing a monolayer of cells with PBS and then incubating for a short time with 0.25% trypsin and 0.02% EDTA. Cells were then pooled, washed 2 times by centrifugation, and resuspended in PBS. A small amount of the cell suspension was stained with 0.2% trypan blue salt solution, cells were examined on a hemocytometer, and cell number and viability were determined. See Kerley-Hamilton et al (2005) p53-dominant negative to positive in a stationary vane cell tubular machinery-destructive negative molecular truck, and Cheol et al (2005) indication of apoptosis and inhibition of cycloosygenase-2 expression by N-methyl-N' -nitro-N-nitro-illustrative in a human leukoderma cell.

The results of cell proliferation assays for different cell lines are presented in FIGS. 1-10.

Example 2

Detection of cell proliferation Using BrdU-ELISA

Cells were incubated in a black 96-well MP (tissue culture grade; clear flat bottom) at a final volume of 100. mu.l/well in the presence of different concentrations of test substance (drug) in a humidified atmosphere at 37 ℃. If the cells were cultured at 100. mu.l/well, BrdU labeling solution (final concentration: 10. mu.M BrdU) was added at 10. mu.l/well and the incubation of the cell stem was continued at 37 ℃ for 2 to 24 hours (BrdU labeling solution was added at 20. mu.l/well if the cells were cultured at 200. mu.l/well). MP was centrifuged at 300 Xg for 10 min and the labeled medium was removed by pipetting. The cells were dried with a blower for about 15 minutes, or at 60 ℃ for 1 h. FixDenat was added to the cells at 200. mu.l/well and incubated at 15-25 ℃ for 30 minutes. The fix denat solution was completely removed by flicking and tapping. anti-BrdU-POD working solution was added at 100. mu.l/well. Incubate at 15-25 ℃ for about 90 minutes. Alternatively, the incubation time may be between 30-120 minutes, depending on the particular requirements. The antibody conjugate was removed by flicking and each well was washed three times with 200-. The wash solution was removed by tapping. The transparent bottom was sealed with a black adhesive foil and the substrate solution was added to each well at 100. mu.l/well using a multichannel pipettor. The light emission of the sample was measured using a microplate photometer with photomultiplier tubes.

The results of this cell proliferation assay using different cell lines and drugs are shown in figure 11.

Example 3

Design of experiments

Is divided into	Mode of implantation	Number of implanted cells	Number of mice	Number of tumors required	Treatment (twice daily)
						1	Under the skin	2×107	20	10	Is free of
2	Under the skin	2×107	20	10	Vehicle (10% DMSO in saline)
						3	Under the skin	2×107	20	10	BP + BSO (175mg/kg +220mg/kg) orally administered
4	Under the skin	2×107	20	10	BA (5g/kg) intraperitoneally
						5	Under the skin	2×107	20	10	Combo＊(30mg/kg) intraperitoneal and oral administration

^*BP + BSO and BA combination

100 female NU/NU-nubR mice (Charles River, 5-6 weeks) were implanted with 0.72mg 17-. beta.estradiol (human) pellets (pellet) and ear-labeled with clips and weighed 24-48 hours prior to tumor cell implantation. Tumor cells BT474 (2X 10)⁷Cells/mouse) were injected into the subscapular mammary fat pad (0.2ml volume). Calipers were started on day 21 and measured three times per week thereafter (monday, wednesday, friday). Animals were divided by the presence or absence of tumor and tumor volume. Animal body weights were measured 2 times per week starting at week 3 post-implantation (monday and friday). When the tumor size is 150-³(length × width × height) the drug treatment was started. The drug and vehicle administration was tube fed twice daily (BP + BSO), i.p. injection once daily (BA), for 5 consecutive days. Two days of rest period were allowed before the next cycle started. Experimental plan animals received three cycles (5 days each) of treatment if no unexpected toxicity occurred. Animal euthanasia criteria were weight loss of 15% over initial weight or the appearance of certain symptoms. The drug was administered by gavage and intraperitoneally in a volume of 5 ml/kg. The drug and carrier were stored at 4 ℃ in foil-covered vials. The results of this experiment are shown in fig. 12.

Example 4

The effect of the compounds was evaluated using human ovarian cancer cells (OVCAR) xenografted nude mice.

Female NU/NU 37-BU-04-BAC mice (Charles River, 5-6 weeks) were ear-labeled with clamps and weighed 24-48 hours prior to tumor cell implantation. Tumor cells Ovcar3 (5X 10)⁶Cells/mouse) was subcutaneously implanted into the subscapular mammary fat pad of a female nude mouse host. Calipers were started 7 days after tumor cell implantation and measured twice weekly thereafter (monday and friday). Animals were divided by the presence or absence of tumor and tumor volume. Animals were weighed once a week. Drug treatment was started when the maximum diameter of the tumor was 0.4-0.5 cm. 4-iodo-3-nitrobenzamide (BA) (dissolved in 50. mu.l 100% DMSO/mouse) and vehicle (50. mu.l 100% DMSO/mouse) were injected intraperitoneally twice daily for 5 consecutive days. Two days of rest period were allowed before the next cycle started.

Design of experiments

Is divided into	Implantation method	Number of implanted cells	Treatment method
				1	Under the skin	5×106	Carrier X2 (50. mu.l 100% DMSO/mouse)
2	Under the skin	5×106	BA 25mg/kg X2/day (50. mu.l of 100% DMSO solution/mouse)
				3	Under the skin	5×106	BA 50mg/kg X2/day (50. mu.l of 100% DMSO solution/mouse)
4	Under the skin	5×106	None (control)

The results of the experiment are shown in fig. 13 and 14.

Example 5

The purpose of this experiment was to evaluate the efficacy of the coumarin analogue 6-amino-5-iodo-2H-1-benzopyran-2-one (BP) on breast (MDA MB231) cancer nude mouse xenografts.

Female tumor-bearing mice were treated with BP (2 dose levels) weekly for 5 days, monday through friday. The experiment was divided into two tasks: task 1 was to test the effect of pretreatment of the animals with BP prior to tumor implantation, and task 2 was to test the effect of starting treatment after tumor formation. In task 1, female nude mice were pretreated with BP (300 or 1000mg/kg) for one week, followed by subcutaneous implantation of tumor cells, and continued with oral doses of corn oil: animals were treated with PEG 400 or BP for 4-8 weeks. In task 2, BP was compared to the chemotherapeutic drugs used clinically. Tumor of 20-30mm³Female nude mice (MDA MB231) were treated with oral doses of corn oil: PEG 400, BP or Cyclophosphamide (CTX, positive control for MDA MB231) treatment 5 times per week. Treatment of MDA MB231 tumors continued until tumors reached more than 1600mm per animal³Or ulceration occurs. Some MDA MB231 tumors did not reach 1600mm in task 2³. Follow-up of the shrinking tumor lasted 3 months.

MDA MB231 breast tumors responded to BP and CTX (positive control) treatment. In task 1, 300mg/kg and 1000mg/kg of BP inhibited tumor formation in 2/9 and 2/10 animals, respectively. All 8 control animals developed tumors. In task 2, animals treated with BP (1000mg/kg or 2000mg/kg body weight) resulted in 3/5 tumor shrinkage.

General procedure

MDA MB231 human breast cancer cells were injected subcutaneously into the right flank of female nude mice. In task 1, BP administration was performed for 5 consecutive days prior to tumor cell implantation, followed by 5 consecutive days per week for 4-8 weeks. In task 2, when the mean tumor volume reached 50-60mm³The cancer cells were injected, the mice were grouped into 8 groups, corn oil was used: PEG 400 (control), BP or CTX (positive control for MDA MB231) were treated. Tumor volume was monitored for 90 days after drug treatment initiation (for MDA MB 231).

Experimental procedures

Cell lines

MDA MB231 was a human breast cancer cell line established in 1973 from pleural effusion of a patient who received 5-FU, doxorubicin, methotrexate and CTX treatment 3 months prior to the initiation of cell line establishment. The cell line is estrogen receptor negative and has been used for screening non-hormone antagonist targeted anticancer drugs. MDA MB231 in the presence of 1.5g NaHCO₃Growth in Dulbecco's Modified Eagle Medium (DMEM) at 37 ℃ with 5% CO, 10% Fetal Bovine Serum (FBS) and 2mM L-glutamine₂Air in a humid incubator. No antibiotics were added to the medium.

Animal tumor model

4-5 week old Swis NCr female nude mice (nu/nu) were purchased from Taconnic (Germantown, NY). Animals were housed in cages with top sterile filters in clean isolation rooms purchased from Bio Bubble, Inc (Fort Collins, CO), 3 per cage. Upon arrival, four working days were isolated prior to use. The room temperature was maintained at 72 + -5 degrees Fahrenheit and the relative humidity at 35-70% for a 12 hour light/dark cycle. Mice were ad libitum fed standard autoclaved Purina rodent chow. The drinking water was autoclaved acidified water, the water source was recycled, deionized, UV irradiated and5 μ M filtered.

After the isolation of the animals was completed, 1 or 5X 10 subcutaneous injections were administered to the right flank of the mice⁶MDA MB231 cells (0.1ml injection volume). In task 1 mice received 5 days of pretreatment prior to cell injection. Tumor size and body weight were measured 2 times per week. The dimensions of the three planes of the tumor were measured using a vernier caliper and the tumor volume (V) was calculated as follows: v ═ pi (x × y × z)/6, where x, y, and z are tumor measurements minus skin thickness. At the end of the experiment, by CO₂Mice were sacrificed by aspiration and cervical dislocation.

Medicine

BP was formulated with corn oil to PEG 400 (2: 1, V/V) at 30mg/ml and 100 mg/ml. The drug is a suspension at this concentration. Positive control drugs were formulated with Phosphate Buffered Saline (PBS) and 15mg/ml CTX. The drugs were filter sterilized (0.2 μ M filter) prior to use.

Treatment protocol

In task 1, mice to be implanted with MDA MB231 tumor cells were pretreated with BP (300 or 1000mg/kg) for 5 days, after which the cell suspension was injected subcutaneously and drug treatment continued 5 days per week (monday to friday), for a minimum of 4 weeks.

In task 2, when the tumor volume reached a predetermined size (mean tumor volume 50-60 mm)³) Thereafter, the mice were divided into individual treatment groups of 8 mice each. All BP treatments were administered 5 times per week (monday to friday) for at least 4 consecutive weeks. CTX was administered intraperitoneally only once at a dose of 150 mg/kg. All BP treatments were administered orally; for mice implanted with MDA MB231 cellsThe dosage is 1000mg/kg or 2000 mg/kg. For each task, all processing starts on the same day.

After the first drug treatment, tumors were measured 2 times a week for at least 9 weeks (MDA MB 231). The mean tumor volume at each time point was calculated for each group. Specific time points for each group were compared using unpaired two-tailed t-test and the results were analyzed using analysis of variance (ANOVA). In task 2, each tumor volume (V) was expressed as the tumor volume (V) from day 0 (day one treatment)₀) Fraction of the comparison. Average ratio V/V of each group₀The time after treatment is plotted as a function. The response to treatment was determined in two ways, based on the response of the tumor to treatment. For the treatment-responsive groups, a linear regression was performed on the log (tumor volume) -time function plot to determine the Volume Doubling Time (VDT) and the Volume Quadrupling Time (VQT) for each tumor. Tumor growth delay was determined for each treatment group and differences between groups were analyzed using ANOVA.

Systemic toxicity was assessed by weight loss after treatment. Mice were sacrificed at the end of the observation period, or the tumor volume reached 1600mm³Or the tumor can be killed in advance when ulceration occurs.

Statistical analysis

The above statistical analysis was performed using InStat (Graphpad Software, San Diego, Calif.).

Tumor growth

MDA MB231 tumors were measurable within 3 weeks after tumor cell injection, and grew very slowly with a doubling time of 7 days. These values were calculated from the control data. The average tumor volume and body weight at the start of treatment are listed in table 1 (task 1) and table 2 (task 2).

TABLE 1
			Mouse parameters at the beginning of treatment-task 1
Treatment group	Tumor volume (mm)3±SEM*)	Mouse body weight (g + -SEM)*)
			PBS (control)	0	24.0±0.8
MDA MB 231
			300mg/kg	0	24.6±0.9
1000mg/kg	0	23.6±0.7

^*Standard error of SEM ═ mean

TABLE 2
			Mouse parameters at the beginning of treatment-task 2
Treatment group	Tumor volume (mm)3±SEM*)	Mouse body weight (g + -SEM)*)
			MDA MB 231
Corn oil (control)	19.1±5.1	24.4±0.54
			1000mg/kg	24.4±5.8	24.5±0.7
2000mg/kg	23.5±5.8	23.0±0.8
			CTX，150mg/kg	24.0±4.4	23.8±0.4

^*Standard error of SEM ═ mean

Response of tumors to treatment

As a result of the pre-treatment of the mice implanted with MDA MB231, the formation of a tumor was prevented in 1/9-treated mice, and a small tumor appeared to regress, which had grown to 10mm before it disappeared³The size of (2). 1000mg/kg BP-pretreated mice prevented tumor growth in 2/10 animals (20%), and one grew to 195mm on day 63³The tumor of (2) was reduced to 93mm on the 86 th day of the end of the experiment³. Assuming that non-tumor-forming animals survive for 6 months (180 days), the mean survival time of 1000mg/kg BP-pretreated animals is 115 days compared to 72 days (p ═ 0.01) in the control group.

MDA MB231 tumors in task 2 responded to both treatments. CTX (150mg/kg) and BP (1000 or 2000mg/kg) substantially slowed tumor growth, with complete regression induced by both drug treatments. 2 animals treated with 1000mg/kg BP showed no reduction in tumor growth rate compared to control, while 2 tumors completely regressed. All 3 animals in the 2000mg/kg BP-treated group had a shrinkage of the implanted tumor. Treatment was stopped on day 42, when 2 tumors had completely regressed and one relatively large tumor began to shrink (310 mm on day 31)³163mm on day 45³). None of the fully regressed tumors started to re-grow again within the 3 month follow-up period, whereas the partially regressed tumors started to re-grow after the end of the treatment and reached 1835mm at the end of the experiment³The size of (2). The survival time of the 2000mg/kg BP treated animals tended to be prolonged.

The results of the experiment are shown in fig. 15 and 16.

Example 6

Non clinical toxicology

Non-clinical toxicology programs that support oncological applications of 4-iodo-3-nitrobenzamide (BA) include acute (single dose), two-week (multiple dose), dose range, and multiple dose (4-week) toxicology experiments in rats and dogs, wherein BA is administered intravenously. The BA used in the experiment was formulated in β -hydroxypropyl cyclodextrin (25%) (Kleptose).

A defined 4-week experimental study included BA dosing 2 times per week at a dose of 60 mg/kg/day, including comprehensive clinical evaluation and/or microscopic examination of all tissues listed. Multi-dose experiments in dogs included electrocardiography and physical examination, including heart rate, respiratory rate, and body temperature measurements. Toxicokinetic data were also collected in a 4-week multi-dose study in rats and dogs. In addition, two specific experiments were performed, one in vitro hemolytic capacity/plasma compatibility studies using dog and human blood and plasma, and the other in intravenous local tolerability studies in rabbits. A single dose study was also performed in rats to evaluate the effect of dosing rate on the neurobehavioral effects induced by BA in this model.

In rats and dogs, BA was well tolerated at single intravenous doses up to 50 mg/kg. At a single bolus intravenous dose of 100mg/kg, clinical signs were observed, including rat twitching and ataxia in dogs. Repeated doses of 100mg/kg caused clinical changes in dogs, mainly including hypersalivation, weight loss and reduced food intake.

Example 7

Title: phase a 1, the first phase of the open-label human dose escalation study, the safety and pharmacokinetics of BA were evaluated in patients with advanced solid tumors.

And (3) a research stage: 1

Indications are as follows: treatment of advanced solid tumors

The primary purpose is as follows: adult patients with histology demonstrated advanced solid tumors and ineffective standard therapy or no standard therapy were selected, after intravenous administration of BA, the safety of BA was assessed, the Maximum Tolerated Dose (MTD) was established, and a pharmacokinetic profile of BA was established.

For the second purpose: subjects with detectable disease were evaluated for response (according to RECIST criteria). Establishing a safety curve: significant laboratory changes and Adverse Events (AEs) not defined as dose-limiting toxicity (DLT).

Exploratory purposes: the effect of the treatment on biomarkers of the tumor status is evaluated.

Experiment design: phase a 1, the first phase of the published human dose escalation study, is designed to determine the safety, MTD and PK profiles of BA. BA was administered intravenously twice weekly (day 1 and day 4 of the week) for 3 weeks, followed by a one week rest period without BA treatment, one cycle every 28 days. Cycle one (day 1 to day 28) is defined as the experimental safety period during which the MTD of the drug is determined. The remainder of the experiment is referred to as the maintenance period. Subjects may be involved in the study until drug intolerance or disease progression occurs.

The safety evaluation was performed following the guidelines of Cancer Therapy evaluation program Common Telematics Criterion for Addition Events (CTCAE), version 3.0, month 12, 2003. For detectable disease, the first assessment of tumor response was performed at study week 8, approximately every 8 weeks thereafter. Disease progression is established using revised responseeevaluation criterion in Solid turbines (RECIST) Criteria. For undetectable diseases, the time to disease progression is determined using best medical practice.

A first end point and a second end point: the first endpoint was safety/tolerability, used to characterize DLT and PK curves: BA half-life (t)_1/2) Maximum observed concentration (Cmax), area under the plasma concentration-time curve (AUC), and Clearance (CL).The second endpoint was tumor response evaluated according to RECIST criteria; a safety curve; significant laboratory changes and other AEs (not defined as DLT). The exploratory study was a reduction in Circulating Tumor Cell (CTC) levels.

Sample size: 36 subjects were expected to participate in the study. Subjects were assigned to a continuous cohort (cohort) of 1, 3 or 6 subjects at different dose levels. 10 dose cohorts may be required to determine the MTD.

Summary of subject eligibility criteria:

the addition criteria include: (a) age > 18 years, pathologically proven advanced solid tumors and standard treatment ineffective or no standard therapy, (b) Eastern Oncology cooperative Group (ECOG) performance status < 2, and (c) Absolute Neutrophil Count (ANC) > 1.5 × 10⁹L (no GCF support during the first 2 weeks of study day 1); platelet number not less than 100.0 × 10⁹L (no blood transfusion during the first 2 weeks on study day 1); and hemoglobin is greater than or equal to 9.0g/dL (allowing the use of erythropoiesis stimulating drugs).

The exclusion criteria include: subjects are participating in additional study design or drug trials, or are receiving other trial drugs; hematological malignancies; symptomatic or untreated brain metastases require concurrent treatment, including but not limited to surgery, radiation therapy, and corticosteroids; the history of epilepsy; study MI, unstable angina, Congestive Heart Failure (CHF), New York Heart Association (NYHA) > grade II, uncontrolled hypertension in the first 6 months on day 1; anticoagulant therapy is ongoing or prior (within the first 7 days of study day 1); is undergoing specific drug therapy (see subsection 4.2.3); serum creatinine > 1.5 × ULN; elevated liver enzymes (AST/ALT) > 2.5 × ULN, or > 5.0 (if secondary to liver metastasis), alkaline phosphatase > 2.5 × ULN, or > 5.0 (if secondary to liver or bone metastasis); total bilirubin > 1.5 × ULN; systemic chemotherapy was present during the first 28 days of study day 1 (during the 42 day washout period for BCNU or mitomycin C); study day 1 was over-radiotherapy within the first 28 days; study ofAntibody treatment for the malignant disease is carried out within the first 1 month of 1 day; and chemotherapy is being performed with any other drug than BA or radiation therapy is not allowed during the study.

Dose and administration of the experimental drugs: BA was provided in a 10mL vial at a concentration of 10 mg/mL. It is estimated that 10 queues are required for determining the MTD.

Initial dose (cohort A): in cohort a, one subject received BA administration at a dose level of 0.5mg/kg (based on body weight weighed at screening) twice a week. If the subject has a level 2 or greater toxic response, then 3 additional subjects are added to the queue. If the cohort had no additional subjects at this dose presenting DLT, dose escalation was performed as follows. If the initial subject did not develop a DLT, dose escalation was performed as follows.

Dose escalation before grade 2 toxicity (Perhaps cohort B-J): unless subjects develop grade 2 or greater toxicity, one subject will be initially enrolled in all consecutive cohorts with a planned 100% increase in dose level, with possible expansion of cohorts as described in cohort a. After 6 BA doses, the safety data were checked and if no subjects had grade 2 or more toxicities, it was decided to add to the next cohort. If one subject in the queue is toxic at a level of 2 or more, then 3 additional subjects are added to the queue. If the cohort does not have any more DLTs present in the other three subjects at this dose, further dose escalation can be performed. If 1 of these 3 persons had a DLT, then 3 more subjects were placed in the same cohort at the same dose. If none of these 3 persons had a DLT, dose escalation was continued. If one or more subjects in the cohort develop a DLT, the previous lower dose level is determined to be the MTD. Subjects under MTD may be increased if necessary to ensure that at least 18 subjects in the study receive BA treatment.

Dose escalation following grade 2 toxicity level (possible cohorts B-J): escalation and elimination of the dose related initial grade 2 toxicity for the next levelAfter dosing, three subjects will be initially enrolled in all subsequent cohorts (cohort B, C, D, E, F, G, H, I or J) studies. If no one of the 3 initial subjects had a DLT, then dose escalation was performed to the next cohort. If 1 of 3 presented a DLT, then another 3 subjects were added to the same cohort at the same dose. If no one of the 3 people has a DLT, the increment is continued. If another subject or subjects in the cohort develop a DLT, the previous lower dose level is determined to be the MTD. Study subjects at MTD may be added if necessary to ensure that at least 18 subjects in the study receive BA.

Dose escalation in a subject: once a BA dose level is confirmed to be safe and tolerable according to the above criteria, all subjects receiving the lower dose should be suitably escalated to the highest safe dose (as determined by the primary investigator). Once the MTD is determined, all subjects in the study should be appropriately incremented to receive the MTD.

Total dose escalation limitation: if grade 2 toxicity is observed and the dose level is subsequently cleared, then individual dose escalation between cohorts should be more conservative, should be limited to a maximum increase of about 40% over the previous dose level until grade 3 toxicity is observed, and subsequent dose escalation should be limited to a dose escalation of about 25%. Absolute dose escalation should be determined by the safety observation group after reference to all available data.

Control group: is free of

The procedure is as follows:

screening: pre-addition screening tests and evaluations were only performed after obtaining written Institutional Review Board (IRB) approved informed consent signed by each subject. The entire procedure should be performed within the first 2 weeks of study day 1, unless otherwise specified. Clinical assessments included complete medical history, physical examination, ECOG status, height, weight, vital signs and concomitant medication. Laboratory examinations included hematology (sorting, reticulocyte count, and platelets); prothrombin Time (PT) and partial procoagulantZymogenic kinase time (PTT); biochemical complete set (sodium, potassium, chlorine, CO)₂Creatinine, calcium, phosphorus, magnesium, BUN, uric acid, albumin, AST, ALT, alkaline phosphatase, total bilirubin, cholesterol, HDL, and LDL), urinalysis by microscopy, serum tumor markers, serum or urine pregnancy tests on potentially pregnant women. Cardiac functional examinations included Creatine Kinase (CK) and 12-channel Electrocardiogram (EKG). Clinical staging included imaging of detectable disease by Computed Tomography (CT) or Magnetic Resonance (MRI) within the first 4 weeks of study day 1. Clinical staging data for undetectable disease may occur.

Treatment of: eligible subjects were included in the study and received study medication on the first day. Pre-and post-dose trials were performed as described in the study protocol. BA was administered twice weekly on days 1, 4,8, 11, 15 and 18 of each 28 day cycle; the infusion time for administration was 2 hours. On day 29, subjects began cycle 2 and continued dosing on days 1, 4,8, 11, 15 and 18 of this and each subsequent cycle. Subjects may be consistently engaged in the study until drug intolerance or disease progression occurs or withdrawal willingness is indicated. Subjects who meet RECIST revision criteria for disease progression may continue the study if they prove clinically beneficial.

For detectable disease, the planned first tumor response measurement should be taken at week 8 of the study (study day 50 ± 5), every 8 weeks thereafter. Disease progression was established by CT or MRI (the same techniques must be used as at screening) using tumor responses based on the revised reponseevaluation Criteria in Solid Tumors (RECIST) Criteria. For undetectable diseases, the time to disease progression is determined using best medical practice.

End of study: each subject should end the study procedure as described in the experimental protocol, and completed within 30 days after the last BA administration. In addition, subjects were also evaluated for overall tumor response by clinical imaging if they were not evaluated within 30 days prior to the last BA administration.

Statistical description: descriptive statistics will calculate safety, PK and PD endpoints. The reaction data establishing the time of progression are reported in tabular form. Tumor progression data were classified according to revised RECIST criteria.

PK parameters were estimated using a non-chamber model. PK parameters are described by arithmetic mean, standard deviation, coefficient of variation, maximum, minimum, median and geometric mean. Statistical calculations were performed using the SPlus 5.1 version (or more recent version).

Data analysis can also be carried out, where appropriate, by nonlinear mixed-effect modeling (population method) to compartment analysis. Other analyses are suitably performed descriptively.

The results were analyzed after all subjects received BA for MTD dose levels (or the highest dose level received in the study) for at least one cycle (6 doses). This coincides with the end of the safety period of the study. Other analyses may be performed on the ongoing basis as necessary to provide information for later experimental design.

The above examples are in no way limiting to the scope of the invention. Furthermore, those skilled in the art will recognize that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims, which are within the scope of the present invention.

It will be apparent to those of ordinary skill in the art that numerous changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims (16)

1. Use of a compound of the formula or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating ovarian cancer in a subject in need thereof

2. The use of claim 1, wherein the ovarian cancer is ovarian adenocarcinoma.

3. The use of claim 2, wherein the ovarian cancer is an ovarian adenocarcinoma that has metastasized intraperitoneally.

4. The use of any one of claims 1-3, wherein the treatment further comprises surgery, hormonal therapy, radiation therapy, chemotherapy, gene therapy, immunotherapy, or a combination thereof.

5. The use of claim 4, wherein the treatment further comprises surgery.

6. The use of claim 4, wherein the treatment further comprises radiation therapy.

7. The use of claim 4, wherein the treatment further comprises combination drug therapy.

8. The use of claim 7, wherein the combination therapy comprises administration of one or more anti-tumor chemotherapeutic, chemopreventive, side-effect-limiting agents, or a combination thereof.

9. The use of claim 8, wherein the one or more anti-neoplastic chemotherapeutic agents are selected from the group consisting of alkylating agents, antimetabolites, natural antineoplastics, hormonal antineoplastics, angiogenesis inhibitors, differentiating agents, RNA inhibitors, antibodies or immunotherapeutics, gene therapy agents, small molecule enzyme inhibitors, biological response modifiers and anti-metastatic agents.

10. The use of claim 8, wherein the one or more anti-tumor chemotherapeutic is selected from the group consisting of cyclophosphamide, etoposide, altretamine and ifosfamide.

11. The use of claim 8, wherein the combination therapy comprises administration of one or more chemopreventive agents.

12. The use of claim 9, wherein the combination therapy comprises administration of one or more chemopreventive agents.

13. The use of claim 10, wherein the combination therapy comprises administration of one or more chemopreventive agents.

14. The use of claim 8, wherein the combination therapy comprises administration of one or more side-effect limiting agents.

15. The use of claim 9, wherein the combination therapy comprises administration of one or more side-effect limiting agents.

16. The use of claim 10, wherein the combination therapy comprises administration of one or more side-effect limiting agents.