CN116726008A - Use of anastrozole in the preparation of drugs for the treatment of lymphoma - Google Patents

Abstract

The invention discloses an application of anastrozole or pharmaceutically acceptable salt, solvate or hydrate thereof in preparing a medicament for treating lymphoma. Experiments prove that anastrozole or pharmaceutically acceptable salt, solvate or hydrate thereof can be used for treating lymphoma, in particular diffuse large B cell lymphoma accompanied by c-MYC rearrangement.

Description

Use of anastrozole in the preparation of drugs for the treatment of lymphoma

Technical field

The present invention belongs to the field of medical technology, and specifically relates to the use of aromatase inhibitor anastrozole or its pharmaceutically acceptable salt, solvate or hydrate in the preparation of drugs for treating lymphoma.

Background technique

Anastrozole compound (chemical name: α,α,α′,α′-tetramethyl-5-(1H-1,2,4-triazole-1-methyl)-1,3-benzenediactonitrile ; English name: Aanastrozole) is an aromatase inhibitor. Aromatase inhibitor (aromataseinhibitor, AI) can specifically cause aromatase inactivation, block aromatization reaction, inhibit estrogen production, and reduce blood levels of Estrogen levels thus achieve the purpose of treating breast cancer. It is mostly used in postmenopausal patients with advanced breast cancer who have failed anti-estrogen (tamoxifen) treatment. Anastrozole is currently mainly used clinically for the treatment of advanced breast cancer in postmenopausal women.

Anastrozole structural formula

c-MYC is a proto-oncogene located on chromosome 8q24, encoding a transcription factor and involved in many processes such as cell growth, proliferation, differentiation, and apoptosis. 10%-15% of newly diagnosed patients with diffuse large B cell lymphoma (DLBCL) have potential MYC translocation, leading to dysregulation of cell proliferation and apoptosis. BCL-2 is a proto-oncogene located on chromosome 18q12, and the encoded protein has an important anti-apoptotic effect. In DLBCL, overexpression of BCL-2 gene not only inhibits the apoptosis of tumor cells, but also often cooperates with c-MYC or other oncogene genes to promote the progression of DLBCL and mediate drug resistance in DLBCL cells. The BCL-6 gene is a transcriptional repressor located on chromosome 3q27, which mainly regulates cell proliferation, differentiation and apoptosis. Gene translocation related to BCL-6 down-regulates the expression of BCL-6 protein in normal germinal center B cells, causing the inhibitory effect of BCL-6 on MYC and BCL-2 to fail and causing lymphoma. Approximately half of patients with c-MYC translocations also have BCL-2 and/or BCL-6 translocations. In the latest 2016 WHO classification, DLBCL with the above-mentioned recurring genetic abnormalities is defined as high-grade B-cell lymphoma (HGBCL) with MYC and BCL-2 and/or BCL-6 translocations. , these patients account for approximately 8%-10% of all newly diagnosed DLBCL patients. Compared with other types of DLBCL, this type is more aggressive. After receiving first-line treatment with R-CHOP, the efficacy is often poor and the prognosis of patients is extremely poor.

Patients with c-MYC/Bcl-2 rearranged DLBCL have high-risk clinical characteristics and are prone to relapse and drug resistance. Even with high-intensity chemotherapy regimens, patients still fail to obtain a better prognosis. Currently, there is no consensus on the optimal treatment for this type of lymphoma. At present, international research on this type of lymphoma has fallen into a bottleneck zone. How to discover new relevant pathways and drug-related targets, and ultimately provide safe, effective and cheap drugs for the whole society, is an important issue for both basic and applied research on biomedicine in my country. issues of great significance. Faced with the international trend of increasing investment in the research and development of new drugs for corresponding targets year by year and the risk of failure increasing year by year, discovering new indications for existing drugs (new uses of old drugs or drug repositioning) can effectively avoid R&D risks to a certain extent. Reducing R&D costs and accelerating the pace of drug launch to quickly meet clinical drug needs has become a strategy that many international pharmaceutical companies attach importance to and adopt.

"Comparative functional genomics" can break the analytical barriers that make it difficult to jointly apply multi-omics data and realize the organic combination of "disease-gene-drug". Applying this method and clinical bioinformatics strategy, we can discover compounds that may potentially treat c-MYC/Bcl-2 rearranged DLBCL from many already on the market, greatly reducing the number of experimental screening compounds and saving financial resources and manpower. And the treatment effect is better. There are no reports on the use of anastrozole in the treatment of lymphoma.

Contents of the invention

According to one aspect of the present invention, an object of the present invention is to provide the use of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a medicament for treating lymphoma.

Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

According to another aspect of the present invention, another object of the present invention is to provide anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof and an additional anti-cancer therapeutic agent in combination for the preparation of a medicament for the treatment of lymphoma uses in. The additional anti-cancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide.

Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

According to another aspect of the present invention, another object of the present invention is to provide the use of a pharmaceutical composition in the preparation of a drug for treating lymphoma, the pharmaceutical composition consisting of the active ingredient anastrozole or a pharmaceutically acceptable salts, solvates or hydrates and pharmaceutically acceptable excipients or carriers. Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

Preferably, the pharmaceutical composition contains 1-99 wt% of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof and 1-99 wt% of a pharmaceutically acceptable excipient or carrier.

Preferably, the pharmaceutical composition can be prepared into tablets, capsules, pills, powders, immediate release dosage forms, sustained release dosage forms, solutions, suspensions, emulsions, ointments, creams or suppositories, etc. Preferred are tablets, capsules, pills, powders, immediate release dosage forms, sustained release dosage forms, solutions, and suspensions.

Preferably, the dosage of the pharmaceutical composition is determined according to the patient's age, condition, etc., and the unit dose of the formula contains 0.05-200 mg of the anastrozole or its pharmaceutically acceptable salt, solvate or hydrate. , preferably, the unit dose of the formulation contains 1 mg to 100 mg of said anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Preferably, the usual daily dose of the pharmaceutical composition is 0.001-100 mg/kg body weight, preferably the daily dose is 0.1-20 mg/kg body weight, and is taken in one go or in divided doses.

According to another aspect of the present invention, another object of the present invention is to provide a method for treating lymphoma, said method comprising administering to a patient a therapeutically effective amount of anastrozole or a pharmaceutically acceptable salt or solvate thereof Or hydrate or said pharmaceutical composition. Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

Description of drawings

In order to more clearly explain the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings that need to be used in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description The drawings illustrate some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without exerting any creative effort.

Figure 1 shows the volcano plot of differential expression analysis of transcriptome sequencing data of GSE44164 double-hit lymphoma patients, and 835 differential genes were screened out, including 521 up-regulated genes and 314 down-regulated genes.

Detailed ways

Hereinafter, the present invention will be described in detail. Before proceeding to the description, it is to be understood that the terms used in this specification and the appended claims should not be construed to be limited to ordinary and dictionary meanings, but rather to allow the inventor to appropriately define the terms for best interpretation. On the basis of the principles, explanations are made according to the meanings and concepts corresponding to the technical aspects of the present invention. Accordingly, the descriptions set forth herein are preferred examples for illustrative purposes only and are not intended to limit the scope of the invention, so that it will be understood that others may be derived therefrom without departing from the spirit and scope of the invention. price or improvement methods.

As used herein, the terms "includes," "includes," "has," "contains," or any other similar terms are open-ended connectives intended to cover a non-exclusive inclusion. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not expressly listed but that are generally inherent to the composition or article. Otherwise, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), Both A and B are true (or exist). In addition, in this article, the interpretation of the terms "includes", "includes", "has" and "contains" shall be deemed to have been specifically disclosed and also cover closures such as "consisting of" and "consisting essentially of". formula or semi-closed conjunction.

In this article, all characteristics or conditions defined in the form of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges shall be deemed to cover and specifically disclose all possible subranges and individual values within the ranges, in particular integer values. For example, a range description of "1 to 8" should be deemed to have specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly is a secondary range defined by all integer values and shall be deemed to have been specifically disclosed as individual values within the range such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise indicated, the foregoing method of interpretation applies to all contents of the present invention, whether broad or not.

If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that any pairing of the upper limit of the range or the preferred value and the lower limit of the range has been specifically disclosed herein. or all ranges consisting of better values, whether or not these ranges are separately disclosed. In addition, when reference is made herein to a range of values, such range shall include its endpoints and all integers and fractions within the range, unless otherwise stated.

In this document, numerical values shall be understood to have an accuracy of 100 significant digits, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

definition

The term "pharmaceutically acceptable salts" means salts that are suitable within the scope of sound medical judgment for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc. and with a reasonable benefit/risk ratio Proportionate to those salts. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of anastrozole described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are those prepared with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid). , citric acid, succinic acid or malonic acid) or amino salts formed by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glyceryl phosphate Salt, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactouronate, lactate, lunar silicate, dodecyl Sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxy Naphthoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinate , sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4-salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate , lower alkyl sulfonate and aryl sulfonate.

The term "solvate" refers to a form of a compound that is combined with a solvent, usually through a solvolysis reaction. This physical bonding can include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include stoichiometric and non-stoichiometric solvates. Under certain circumstances, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to separate. "Solvate" includes both solution phase and isolable solvates. Representative solvates include hydrates, ethoxides, and methoxides.

The term "hydrate" refers to a compound that is combined with water. Typically, the number of water molecules contained in a hydrate of a compound is proportional to the number of molecules of the compound in the hydrate. Thus, a hydrate of a compound may, for example, be represented by the general formula _R.xH2O , where R is the compound and x is a number greater than zero. A given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), such as hemihydrate (R·0.5H ₂ O)) and polyhydrates (x is a number greater than 1, such as dihydrate (R·2H ₂ O) and hexahydrate (R·6H ₂ O)).

As used herein, the term "treating" means eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with it. As used herein, the term "treatment" and the like may include "preventive treatment" which refers to reducing the recurrence of a disease or condition in a subject who does not have or is at risk of developing or susceptible to the disease or condition or the recurrence of the disease or condition. The possibility of development or recurrence of a previously controlled disease or condition. The term "treatment" and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. For example, for oral dosage forms of the present invention, an "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

The term "pharmaceutically acceptable excipient or carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers Including water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Pharmaceutically acceptable excipients that may be used in the manufacture of pharmaceutical compositions described herein include, but are not limited to, for example, inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifying agents, disintegrating agents , adhesives, preservatives, buffers, lubricants and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring and perfuming agents may also be present in the compositions.

Pharmaceutical compositions may be formulated for any route of administration, such as oral administration. Typically, pharmaceutical compositions are solid dosage forms. However, in some embodiments, other dosage forms may also be used, such as liquid, suspension, or semi-solid dosage forms.

Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is combined with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and/or (a) a filler or extender ( such as starch, lactose, sucrose, glucose, mannitol and silicic acid), (b) binders (such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic), (c) humectants (e.g. glycerol), (d) disintegrants (e.g. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate), (e) retarders (e.g. paraffin), (f) Absorption enhancers (such as quaternary ammonium compounds), (g) wetting agents (such as cetyl alcohol and glyceryl monostearate), (h) absorbents (such as kaolin and bentonite), and (i) lubricants (such as talc , calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) and mixtures thereof. For capsules, tablets and pills, the dosage form may contain buffering agents.

The term "subject", "patient" or "subject" refers to an animal, preferably a mammal, and most preferably a human, that has been the subject of treatment, observation or experimentation. In any of the embodiments described herein, the subject can be a human.

Various dosage forms of the pharmaceutical compositions of the present disclosure can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the preparation formula contains 0.05-200 mg of the compound. Preferably, the unit dose of the preparation formula contains 1 mg-100 mg of the compound.

The compounds and pharmaceutical compositions of the present disclosure can be used clinically in mammals, including humans and animals, through administration routes such as the mouth, nose, skin, lungs, or gastrointestinal tract. The optimal daily dose is 0.1-20 mg/kg body weight, taken in one go or in divided doses. Regardless of the administration method used, the optimal dosage for the patient will depend on the specific treatment. Clinical trials usually start with a low dose and gradually increase the dose until the most suitable dose is found.

In common embodiments of the treatment methods provided by this disclosure, the abnormal cell growth is cancer. The compounds of the present invention may be administered as a single agent or may be administered in combination with other anti-cancer therapeutics, particularly with standard of care agents appropriate for the particular cancer.

The term "additional anti-cancer therapeutic agent" as used in this disclosure refers to any one or more therapeutic agents, other than the compounds of the invention, that are or can be used in the treatment of lymphoma. In certain embodiments, such additional anti-cancer therapeutics include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, anti-tumor antibiotics, anti-angiogenic agents, topoisomerases I and II Inhibitors, plant alkaloids, hormone agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological Response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxins, immuno-oncology agents, etc. Preferably, the additional anti-cancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide.

In some embodiments, it is provided that administration of the compounds of the present invention can be accomplished by any method capable of delivering the compound to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

The pharmaceutical compositions may, for example, be in a form suitable for oral administration, e.g. as tablets, capsules, pills, powders, sustained release preparations, solutions, suspensions; for parenteral injection, e.g. as sterile solutions, suspensions or emulsion; a form suitable for topical administration, such as as an ointment or cream; or a form suitable for rectal administration, such as a suppository. Preferred are tablets, capsules, pills, powders, immediate release dosage forms, sustained release dosage forms, solutions, and suspensions.

The following examples are merely examples of embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope that do not deviate from the essence and concept of the present invention fall within the protection of the present invention. scope. Unless otherwise stated, the reagents and instruments used in the following examples are all commercially available products.

Example

1. Bioinformatics screening:

1.1 Data sources and screening of differentially expressed genes

The data GSE44164 was screened out from the gene expression profile database (Gene expression, GEO), and the experimental group selected 15 cases of high-grade B cell lymphoma (HGBCL) with Bcl-2/c-MYC rearrangement of GBC subtype. ), its type is diffuse large B cell lymphoma (DLBCL); 13 cases of normal tonsillar germinal center B cells were screened from the gene expression profile data set GSE43677 of the same research group as a control group. Both sets of data set platforms are GPL96[HG-U133A]Affymetrix Human Genome U133A Array.

The obtained data and matrix were read and processed using R1.4.1717 software. After the obtained data sets were grouped, the limma3.49.4 software package was used to screen the data sets for significantly differentially expressed genes. The screening thresholds were P<0.05 and |log2FoldChange|>0.5. The obtained differentially expressed genes (DEGs) were plotted and displayed using the ggplot2 software package.

disease association analysis

1.2 Drug screening

Based on the theories of "systems biology" and "comparative functional genomics", the "integrated multi-omics analysis" algorithm was designed to integrate and analyze the disease or patient transcriptome and drug transcriptome through the above data sources, and established a clinical bioinformatics epicenter. Epigenomic Precision Medicine Prediction Platform (EpiMed). This platform is used to conduct correlation analysis between the above DEGs and drug transcriptome data, and search for drugs that can effectively treat monkeypox virus infection in humans among FDA-approved clinical drugs and traditional Chinese medicines. The screening conditions are correlation coefficient >|0.1|, P<0.05 , among which the drugs with negative correlation are the drugs with therapeutic effect.

2. Experimental verification:

2.1 Experimental materials:

2.1.1 Main reagents: PRIM 1640 culture medium (Gibco Company, USA), fetal calf serum (Gibco Company, USA), penicillin-streptomycin-amphotericin (100X triple antibody) (Gibco Company, USA), CCK-8 kit (Japanese Dojindo Company), Anastrozole (Shanghai Merrill Biochemical Technology Co., Ltd.)

2.1.2 Main instruments: micropipette (2.5ul, 10ul, 20ul, 100ul, 200ul, 1000ul, 5000ul, Eppendorf Company of Germany), ultra-clean workbench (Thermo Fisher Company of the United States), cell culture incubator (ThermoFisher Company of the United States) , microplate reader (Thermo Fisher Company, USA)

2.1.3 Cell line: DOHH-2 (Bcl-2/c-MYC rearranged diffuse large B lymphoma cell line)

2.2 Experimental methods:

2.2.1 Preparation of complete cell culture medium: Take 6 ml of penicillin-streptomycin-amphotericin (100X third antibody) and 56 ml of fetal calf serum, add it to 500 ml of PRIM 1640 culture medium, configure it into a complete culture medium, and store it in a 4-degree refrigerator Save for later use.

2.2.2 Cell culture and passage: The DOHH-2 cell line was cultured in complete culture medium and placed in a 37°C, 5% incubator.

2.2.3 Drug preparation: Use an electronic balance to weigh a certain dose of the drug, use DMSO to dissolve the drug, prepare a 10mmol/L solution, and store it at -30 degrees. When used, the drug is diluted in the culture medium, and the prepared concentrations are 160umol/L, 120umol/L, 80umol/L, 40umol/L, and 20umol/L respectively.

2.2.4CCK-8 experiment: Passage when the cell density reaches about 80%, and the passage ratio is 1:3. After about 3 passages, use serum-free medium to culture for 24 hours, and select cells for CCK-8 experiment. After centrifuging the cells, resuspend the cells in 10 ml of culture medium, add 20 ul of cells to 80 ul of culture medium, and add 10 ul to a cell counting plate to count the total number of cells. Select an appropriate number of cells for the experiment. Each well is inoculated with 100ul of cell suspension. The number of cells in the well is about 5×10 ^4. There are 3 duplicate holes in each group. 100ul of drugs containing different concentrations are added to each well to make the final concentration in the well 80umol/L and 60umol/L. , 40umol/L, 20umol/L, 10umol/L. Add 100ulPBS to the outermost edge of the 96-well plate. Add 20ul of CCK-8 solution to each well at three time points (24h, 48h, and 72h) (the concentration of CCK-8 solution in each well is 10%), shake well and incubate in the incubator for 2 hours, and then read out each reaction using a microplate reader. Measure the OD value of the well at a wavelength of 450 nm, and record the data.

2.2.5 The drug killing inhibition rate is calculated as follows: Drug killing inhibition rate (%) = 1-(mean OD of the experimental group-blank OD)/(mean OD of the control group-blank OD)×100%.

2.2.6 Statistical method: Three independent experiments were conducted, and the results were averaged.

3. Bioinformatics screening results

3.1 Screening results of differentially expressed genes

By analyzing the transcriptome sequencing data of GSE44164 double-hit lymphoma patients, 835 differential genes were screened out (Figure 1, differential expression analysis volcano plot), including 521 up-regulated genes and 314 down-regulated genes.

3.2 Differential gene drug prediction results

Import the above 835 differential genes into EpiMed, and integrate them with the disease or patient transcriptome and drug transcriptome for analysis, and search for drugs that can effectively treat this type of lymphoma among FDA-approved clinical drugs and traditional Chinese medicines. The screening condition is correlation coefficient>| 0.1|, P<0.05, among which the negatively correlated drugs are drugs with therapeutic effects, and anastrozole is screened out as a potential therapeutic drug.

4. Experimental verification of the killing effect of drugs on lymphoma cells

4.1 The prediction results of differential gene drugs are as follows in Table 2

Table 2

first day Inhibition rate 1 Inhibition rate 2 Inhibition rate 3 average 80umol/L 54.58% 52.87% 30.46% 45.97% 60umol/L 46.39% 45.38% 30.97% 40.91% 40umol/L 55.71% 43.91% 26.04% 41.89% 20umol/L 41.26% 27.36% 24.01% 30.88% 10umol/L 31.53% 8.29% 14.33% 18.05% the next day Inhibition rate 1 Inhibition rate 2 Inhibition rate 3 average 80umol/L 69.72% 42.01% 38.18% 49.97% 60umol/L 41.26% 17.09% 16.28% 24.88% 40umol/L 40.37% 16.27% 15.56% 24.06% 20umol/L 40.67% 1.04% 2.17% 14.63% 10umol/L 6.75% -13.91% -10.97% -6.04% The third day Inhibition rate 1 Inhibition rate 2 Inhibition rate 3 average 80umol/L 72.81% 78.90% 72.81% 74.84% 60umol/L 50.95% 53.34% 50.95% 51.74% 40umol/L 37.63% 23.65% 37.63% 32.97% 20umol/L 5.08% 11.10% 5.08% 7.08% 10umol/L -1.90% -10.15% -1.90% -4.65%

Inhibition rate 1, inhibition rate 2, and inhibition rate 3 were repeated experiments three times in parallel, and the final results were averaged. After 24h, 48h, and 72h of anastrozole drug action, as the drug concentration of anastrozole increases, the inhibition of lymphoma cell proliferation gradually increases. The half inhibitory concentration is about 40umol/L, and the inhibitory effect is considerable.

The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person familiar with the technical field can easily think of changes or replacements within the technical scope disclosed by the present invention. are covered by the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the protection scope of the claims.

Claims (10)

1. Use of anastrozole, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the preparation of a medicament for the treatment of lymphoma.

2. The use according to claim 1, wherein the lymphoma is diffuse large B-cell lymphoma accompanied by c-MYC rearrangement.

3. Use of anastrozole, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with an additional anti-cancer therapeutic agent selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, etoposide, for the manufacture of a medicament for the treatment of lymphomas.

4. The use according to claim 3, wherein the lymphoma is diffuse large B-cell lymphoma accompanied by c-MYC rearrangement.

5. Use of a pharmaceutical composition comprising anastrozole as an active ingredient or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable excipient or carrier in the manufacture of a medicament for the treatment of lymphoma; preferably, the lymphoma is diffuse large B-cell lymphoma accompanied by c-MYC rearrangement.

6. The use according to claim 5, wherein the pharmaceutical composition comprises 1-99wt% anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof and 1-99wt% of a pharmaceutically acceptable excipient or carrier.

7. The use according to claim 5, wherein the pharmaceutical composition is formulated as a tablet, capsule, pill, powder, immediate release dosage form, sustained release dosage form, solution, suspension, emulsion, ointment, cream or suppository; preferably in the form of tablet, capsule, pill, powder, quick-release dosage form, slow-release dosage form, solution, or suspension.

8. The use according to claim 5, wherein the pharmaceutical composition is used in an amount depending on the age, condition of the patient, and the unit dose of the formulation comprises 0.05-200mg of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof; preferably, the unit dose of the formulation comprises 1mg to 100mg of said anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof.

9. The use according to claim 5, wherein the pharmaceutical composition is administered in an amount of usually 0.001-100mg/kg body weight per daily dose, preferably 0.1-20mg/kg body weight per daily dose, in one or several doses.

10. A method of treating lymphoma comprising administering to a patient a therapeutically effective amount of anastrozole, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or the pharmaceutical composition for use according to claim 5; preferably, the lymphoma is diffuse large B-cell lymphoma accompanied by c-MYC rearrangement.