MXPA98000945A - Use of griseofulvine to inhibit cancer growth - Google Patents

Abstract

A pharmaceutical composition for the treatment of cancers or tumors in mammals, which comprises griseofulvin, is described. A chemotherapeutic agent may be used in conjunction with griseofulvin, such as enhancers. Griseofulvin can also be used to treat viral infections, either alone or in conjunction with other viral agents or with a potency.

Description

USE OF GRISEOFULVINE TO INHIBIT THE GROWTH OF CANCERS FIELD OF THE INVENTION This invention is a pharmaceutical composition that is useful for the treatment of cancers and tumors, particularly in humans and warm blooded animals. The composition contains griseofulvin. It can also be used in combination with other chemotherapeutic agents.

BACKGROUND OF THE INVENTION Cancers, including leukemia, are the leading cause of death in animals and humans. The exact cause of the leukemia is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of leukemia and tumors have been shown by a number of researchers. Many types of chemotherapeutic agents have been shown to be effective against cancers, tumors and leukemia, but not all types of cancer and tumor cells respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism for the action of these chemotherapeutic agents is not always known.

Despite advances in the field of cancer and leukemia treatments, the main therapies to date are radiation and chemotherapy and bone marrow transplants. The chemotherapeutic approaches are to fight cancers that are particularly aggressive. These cytocidal or cytostatic agents work best in cancers with large growth factors, ie those whose cells divide rapidly. To date, hormones, particularly estrogen, progesterone, and testosterone, and some antibiotics prod by a variety of microbes, alkylating agents, and anti-metabolites form the majority of the therapies available in oncologists. Ideally cytotoxic agents having specificity for leukemia, cancer and tumor cells, while not affecting normal cells, would be extremely desirable. Unfortunately, none has been found and instead agents have been used which especially target rapidly dividing cells (both diseased and normal). Clearly, it would be an advance to develop materials that target cancer or leukemia cells, due to some unique specificity for them. alternatively, materials that were cytotoxic to the leukemia or cancer cells would be desirable, while exerting mild or moderate effects on normal cells. Therefore, it is an object of this invention to provide a pharmaceutical composition that is effective in the treatment of leukemia with mild or no effects on normal blood cells. More specifically, it is an object of this invention to provide a composition comprising a pharmaceutical carrier and a griseofulvin as defined herein in conjunction with a method of treating cancer, leukemia and tumors. The use of griseofulvin in combination with other chemotherapeutic agents that are effective in tumor destruction is a new method of treatment. Griseofulvin can also be used to treat viral infections in the presence of an enhancer.

SUMMARY OF THE INVENTION A pharmaceutical composition for the treatment of mammals, and in particular, warm-blooded and human animals, which are affected by leukemia, this composition comprises a pharmaceutical carrier and an effective amount of griseofulvin. Griseofulvin has the formula: These compositions can be used to inhibit the growth of leukemia, tumor and cancer cells, in humans or animals by administering an effective amount either orally, rectally, topically or parenterally or intravenously These compositions do not significantly affect healthy cells. Enhancers may also be used in combination with griseofulvin, such as chemotherapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION A. DEFINITIONS: As used herein, the term "comprising" means several components that can be used together in the pharmaceutical composition of this invention. Accordingly, the terms "consisting essentially of", "consisting of" are incorporated into the term comprising.

As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without the adverse, undesirable side effects (such as toxicity, irritation, or allergic response) corresponding with a favorable ratio. of benefit / risk. As used herein, the term "safe and effective amount" refers to the amount of a component that is sufficient to produce a desirable therapeutic response without side effects, adverse, undesirable, such as allergic toxicity, irritation or response) corresponding with a reasonable benefit / risk ratio when used in the manner of this invention. The "safe and effective amount", specifies, will obviously vary with factors such as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of the concurrent therapy (if any), and the specific formulations used and the structure of the compounds or their derivatives. As used herein, an "additive, pharmaceutical salt" is the salt of the anti-leukemia compound with an organic and inorganic acid. These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and the like. As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, dispersing agent or vehicle for distributing the anti-leukemia agent to the animal or human. The carrier can be liquid or solid is selected in the planned manner of administration in mind. As used herein, "cancer" or "leukemia" refers to all types of cancers or neoplasm or malignant disease that attacks healthy, normal blood cells or the bone marrow that produces the blood cells found in the mammals. As used herein, "virus" includes viruses that cause disease in warm-blooded animals including HIV, influenza, rhinovirus, herpes, and the like. As used herein, "griseofulvin" means 7-chloro-2 ', 4,6-trimethoxy-6-methylspiro [benzofuran-2- (3H) ,, 1' - [2] cyclohexene] -3,4 ' -Diona. This is an antibiotic substance produced by penicilli um griseofulvum. As used herein, "enhancers" are materials such as triprolidine and its cis-isomer that are used in combination with griseofulvin. The enhancers can suppress the immune system or improve the effectiveness of the drugs. As used herein, "chemotherapeutic agents" includes agents interactive with DNA, anti-etabolites, Interactive Agents with the Tubulin, Hormonal agents and others, such as Asparaginase or hydroxyurea.

B. GRISEOFULVINE Griseofulvin has the following structure: This is prepared according to the method described in the North American Patent No. 3,069,328 issued Hockenhull (1962) and the North American Patent 3,069,328 issued to Dorey et al. (1962).

C. CHEMOTHERAPEUTIC AGENTS The chemotherapeutic agents are generally grouped as DNA-interactive agents, antimetabolites, tubulin-interacting agents, hormonal agents and others such as Asparaginase or hydroxyurea. Each of these groups of chemotherapeutic agents can be further divided by the type of activity or compound. The chemotherapeutic agents used in combination with griseofulvin include the members of all these groups. For a detailed discussion of the chemotherapeutic agents and their method of administration, see Dorr, et al, Cancer Chemotherapy Handbook, 2nd Edition, pages 15-34, Appleton &; Lange (Connecticut, 1994) incorporated herein by reference. Agents interactive with DNA include alkylating agents, for example, Cisplatin, Cyclophosphatic ida, Altretamine; the cleaving agents of the DNA strand, such as Bleomycin; inhibitors of topoisomerase II intercalation, for example, Dactinomycin and Doxorubicin); inhibitors of topoisomerase II not intercalation, such as Etoposide and Teniposide; and Plcamidine a binder of the minor DNA groove. Alkylating agents form covalent chemical adducts with DNA, RNA, and molecular proteins and with smaller amino acids, glutathione and similar chemicals. In general, these alkylating agents react with a nucleophilic atom in a general constituent, such as an amino, carboxyl, phosphate, hydrogen sulfide group, in nucleic acids, proteins, amino acids, or glutathione. The mechanism and role of these alkylating agents in cancer therapy is not well understood. Typical alkylating agents include: Nitrogen mustards, such as Chlorambucil, Cyclophosphamide, Isofamide, Meclorotamine, Melpalano, Uracila mustard; Aziridine such as Tiotepa; methanesulfonate esters such as Busulfan; nitroso-ureas, such as Carmustine, Lomustine, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; bioreductive reduction agents, such as Mitomycin and Procarbazine, Dacarbazine and Altretamine; the cleaving agents of the DNA strand include Bleomycin; inhibitors of DNA topoisomerase II include the following: intercalators, such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone; non-intercalary, such as Etoposide and Teniposide.

The binder of the minor groove of DNA is Plicamycin. Anti-metabolites interfere with the production of nucleic acids by one or the other of the two main mechanisms. Some of these drugs inhibit the production of deoxyribonucleoside triphosphates, which are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently similar to purines or pyrimidines to be able to substitute them in the routes of the anabolic nucleotides. Then, these analogs can be replaced in DNA and RNA instead of their normal counterparts. Anti-metabolites useful herein include: folate antagonists such as metrotrexate and trimetrexate, pyrimidine antagonists, such as Flurouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine and Floxuridine, purine-antagonists include Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin; Modified analogs of sugar include Cyctrabin, Fludarabine; The inhibitors of the ribonucleotide reductase include hydroxyurea.

Interacting agents with tubulin act by binding to specific sites in tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are units of critical cellular structure. When the interactive agents bind to the protein, the cell can not form microtubules. Interacting agents with tubulin include vincristine and vinblastine, both alkaloids and Paclitaxel. Hormonal agents are also useful in the treatment of cancers and tumors. They are used in highly susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and Etinil Estradiol and Diethylstilbesterol, Clortrianisen and Idenestrol; progestins such as caproate Hydroxyprogesterone, Medroxyprogesterone and Megestro; such androgens, testosterone, testosterone propionate; fluoxymesterone, methyltestosterone; Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti-inflammatory benefits as well as the ability of some to inhibit mitotic and halt conversion of DNA synthesis. These compounds include Prednisone, Dexamethasone, Methylprednisolone and Prednisolone.

Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily for the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testicles. Antihormonal antigens include: antiestrogenic agents such as Tamosifene. antidrogenic agents such as Flutamide; and antiadrenales agents such as Mitotano and Aminoglutethimide. Hydroxyurea appears to act primarily through the inhibition of the ribonucleotide reductase enzyme. Asparaginase is an enzyme that converts asparagine to non-functional aspartic acid and thus blocks the synthesis of the protein in the tumor.

D. POTENTIATORS "Enhancers" can be any material that improves or increases the efficiency of the pharmaceutical composition or acts as an immunosuppressant. One such enhancer is triprolidine and its cis-isomer which are used in combination with chemotherapeutic agents and griseofulvin. triprolidine is described in U.S. Patent 5,114,951 (1992). Another enhancer is procodazole, lH-benzimidazole-2-propanoic acid; [ß- (2-benzimidazole) propionic acid]; and 2- (2-carboxyethyl) benzimidazole; propazole] procodazole is an immunoprotective, active, non-specific agent against viral and bacterial infections and can be used with the compositions claimed herein. It is effective with griseofulvin alone in the treatment of cancers, tumors, leukemia and viral infections or in combination with chemotherapeutic agents. Propionic acid and its salts and esters can also be used in composition with those claimed herein. Antioxidant vitamins such as vitamins A, C and E and beta-carotene can be added to these compositions.

E. DOSAGE Any suitable dosage can be given in the method of the invention. The type of compound and the carrier and the amount will vary widely depending on the species of warm or human blood animal, body weight and the type of tumor cancer or viral infection being treated. In general, a dosage of between about 1 milligrams (mg) per kilogram (kg) of body weight and about 8000 mg per kg of body weight is suitable for either griseofulvin or the chemotherapeutic agent. Preferably from 15 mg to about 5000 mg / kg of body weight is used. In general, the dose in man is lower than for small warm-blooded animals such as mice. A dosage unit may comprise a single compound or mixtures thereof with other compounds or other individual cancer compounds. The dosage unit may also comprise diluents, extenders, carriers, liposomes and the like, The unit may be in solid or gel form such as pills, tablets or capsules and the like or in a liquid form suitable for oral, rectal, topical administration , intravenous or parenteral injection or injection in or around the bone marrow. The range and ratio of griseofulvin to the chemotherapeutic agent will depend on the type of cancer or tumor being treated and the particular chemotherapeutic agent.

F. DOSAGE DISTRIBUTION FORMS Chemotherapeutic agents, griseofulvin and, optionally, enhancers are typically mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of administration used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be easily formulated and can be easily processed for swallowing or chewing; other solid forms include granules, and bulk powders. The tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in pharmaceutically acceptable water, fat and oils, alcohols and other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, dispersing agents, diluents, sweeteners, thickeners and melting agents. The oral dosage forms optionally contain flavors and coloring agents. Parenteral and intravenous forms will also include minerals and other materials to make them compatible with the type of injection system or distribution chosen. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate the oral dosage forms for the present invention are described in Robert's North American Patent No. 3,903,297, issued September 2, 1975. The techniques and compositions for to prepare the dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

G. TREATMENT METHOD The treatment method can be any suitable method that is effective in the treatment of the particular type of cancer or tumor being treated. The treatment can be oral administration, rectal, topical, parenteral or intravenous or by injection into the tumor or cancer. The method to apply an effective amount also varies depending on the leukemia, cancer tumor or virus being treated. It is believed that parenteral treatment by intravenous, subcutaneous or intramuscular application of griseofulvin, formulated with an appropriate carrier, additional cancer inhibitor compound or compounds or diluents to facilitate application will be the preferred method of administration of the compounds to the animals of hot blood. In addition to the use of chemotherapeutic agents and enhancers, griseofulvin can be combined with fungicides, herbicides or other antiviral agents. Preferred herbicides and fungicides include carbendazim, fluoconazole, benomyl, glyphosate and propicodazole.

EXAMPLE 1 In an HIV in vitro model, acute, griseofulvin inhibited 98% viral replication in lOμg / ml with a therapeutic index of 5.3. AZT, a known HIV drug, also inhibited 98% viral replication at lμg / ml with a therapeutic index of 12,500. The therapeutic index is the ratio of the toxic dose of the drug to the efficient dose of the drug.

EXAMPLE 2 In an in vivo mouse study for leukemia (P388), griseofulvin showed an increase in survival time relative to an untreated control of 156% at a dose of 4000 mg / kg; 188% at a dose 5000 mg / kg; and of 218% at a dose of 6000 mg / kg.

EXAMPLE 3 In an in vivo study with mice for melanoma (B16), griseofulvin showed an increase in survival time relative to an untreated control of 165% at a dose of 4000 mg / kg; 179% at a dose 5000 mg / kg; and 201% at a dose of 6000 mg / kg. Cytoxan at 300 mg / kg showed an increased survival rate of 192%.

EXAMPLE 4 In an in vitro selection for the WI-38 cell line, type A-1, of Rhinovirus, griseofulvin was effective at 100 μg / ml. The positive control was A-36683 of Abbot Company, (S, S,) -1, 2-bis (5-methoxy-2-benzimidazolyl) -1,2-ethanediol. The A-36683 has a therapeutic index of 1000-3200. Griseofulvin has a therapeutic index of 1-2. (See Schleicher et al, Appli ed Mi crobi ol ogy z 23, No., 1, 113-116 (1972).

EXAMPLE 5 The solid tumors removed from patients are micronized in 2 to 5 mm fragments and placed immediately in the medium of McCoy 5A plus 10% calcine serum nionate, inactivated with heat, plus 1% penicillin / streptomycin. In the space of 4 hours, these solid tumors were mechanically dissociated with scissors, forced through a No. 100 stainless steel mesh, through 25 gauge needles, and then washed with McCoy's medium as described previously. Ascitic, plural, pericardial, and bone marrow fluids are obtained by normal techniques. The fluid or marrow is placed in sterile containers containing 10 units of preservative-free heparin per ml. of fluid or malignant marrow. After centrifugation of 150 x g for 10 minutes, the cells are harvested and washed by McCoy's medium plus 10% calf serum, inactivated with heat. The viability of the cell suspensions in a hemocytomer with trypan blue is determined. The cells to be cloned are dispersed on 0.3% agar in enriched CMRL 1066, supplemented with 15% horse serum, inactivated with heat, penicillin (100 units / ml), streptomycin (2mg / ml), glutamine (2mM) ), insulin (3 units / ml) asparagine (0.6 mg / ml), and HEPES buffer (2mM). For the continuous exposure test, each compound is added to the previous mixture. The cells are placed in 35 mm petri dishes in an upper agar layer on an upper agar layer on an underlying agar layer to prevent the growth of the fibroblasts. Three plates are prepared for each data point. Plates are placed in an incubator at 37 ° C and removed at day 14 for counting the number of colonies on each plate. The number of colonies (defined as 50 cells) formed in the three plates treated with the compound compares the number of colonies formed in the 3 control plates, and the percent of colonies that survive the concentration of the compound can be estimated. 3 positive control plates are used to determine the survival rate. Orthodium vanadate at 200 μg / ml is used as the positive control. If there is less than 30% of colonies in the positive control, when compared to the untreated control, the test is evaluated. At the concentration of 0.5 and 5.0 μl / ml in an individual dose experiment, griseofulvin was not effective (0/1) against the tumors in this test. At a concentration of 50.0 μm / ml in a continuous exposure experiment, griseofulvin was effective against cancers of the colon, lung, non-small areas and ovary. In all, 5 out of 6 had less or equal 50% survival.

Claims (10)

1. CLAIMS 1. A pharmaceutical composition for treating cancer and tumors, comprising a pharmaceutical carrier and from 1 mg / kg to approximately 8000 mg / kg per body weight.
2. 2. A pharmaceutical composition according to claim 1 comprising an enhancer.
3. 3. A pharmaceutical composition according to claim 1 and 2 comprising a pharmaceutically acceptable carrier and a safe and effective amount of griseofulvin and a chemotherapeutic agent.
4. 4. A pharmaceutical composition according to claim 1, 2 or 3, wherein the chemotherapeutic agent is selected from the group consisting of agents interactive with DNA, Anti-metabolites, Interactive agents with Tubulin, Hormone Agents, Asparaginase or hydroxyurea .
5. 5. A pharmaceutical composition according to claim 1, 2 or 4, wherein the chemotherapeutic agent is selected from the group consisting of Asparaginase, Hydroxyurea, Cisplatin, Cyclophosphamide, Altretamine, Bleomycin, Dactinomycin, Doxorubicin, Etoposide, Teniposide and Plcamidine.
6. 6. A pharmaceutical composition according to claim 1, 2 or 4, wherein the chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin, Cictrabine, and Fludarabine.
7. A method for treating cancer or tumors in warm-blooded animals, comprising administering a composition according to claims 1, 2, 3, 4, 5 or 6.
8. 8. A method for treating viral infections in warm-blooded animals comprising administering a composition according to claims 1, 2, 3, 4, 5 or 6.
9. 9. A unit dose composition for treating viral infections in animals or humans comprising a pharmaceutical carrier and from 1 mg / kg to approximately 8000 mg / kg of body weight.
10. 10. A unit dose composition for treating cancer or tumors in animals or humans comprising a pharmaceutical carrier and from 1 mg / kg to approximately 8000 mg / kg of body weight.