Use of anastrozole in preparing a drug for treating lymphoma

Abstract

The present invention discloses the use of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof in preparing a drug for treating lymphoma. Experiments have verified that anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof can be used to treat lymphoma, particularly diffuse large B-cell lymphoma with c-MYC rearrangement.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to the use of an aromatase inhibitor anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a drug for treating lymphoma. Background Art

[0002] Anastrozole compound (chemical name: α,α,α′,α′-tetramethyl-5-(1H-1,2,4-triazole-1-methyl)-1,3-phenylenediacetonitrile; English name: Aanastrozole) is an aromatase inhibitor. Aromatase inhibitor (AI) can specifically lead to aromatase inactivation, block aromatization reaction, inhibit estrogen production, and reduce estrogen levels in the blood to achieve the purpose of treating breast cancer. It is mostly used for postmenopausal patients with advanced breast cancer who have failed anti-estrogen (tamoxifen) treatment. Anastrozole is currently mainly used in the treatment of advanced breast cancer in postmenopausal women.

[0003] Anastrozole structure

[0004] c-MYC is a proto-oncogene located on chromosome 8q24, encoding a transcription factor that participates in many processes such as cell growth, proliferation, differentiation, and apoptosis. 10%-15% of newly diagnosed diffuse large B cell lymphoma (DLBCL) patients have potential MYC translocation, leading to dysregulated cell proliferation and apoptosis. BCL-2 is a proto-oncogene located on chromosome 18q12, and the protein it encodes has an important anti-apoptotic effect. In DLBCL, overexpression of the BCL-2 gene not only inhibits apoptosis of tumor cells, but also often cooperates with c-MYC or other oncogenes 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 translocations related to BCL-6 cause the occurrence of lymphoma by downregulating the expression of BCL-6 protein in normal germinal center B cells, rendering BCL-6 ineffective in its inhibitory effect on MYC and BCL-2. About half of patients with c-MYC translocation also have translocation of BCL-2 and / or BCL-6. In the latest 2016 WHO classification, DLBCL with the above recurrent gene abnormalities is defined as high-grade B cell lymphoma (HGBCL) with translocation of MYC and BCL-2 and / or BCL-6, accounting for about 8%-10% of all newly diagnosed DLBCL patients. Compared with other types of DLBCL, this type is more aggressive, and after first-line treatment with R-CHOP, the efficacy is often poor, and the prognosis of patients is extremely poor.

[0005] DLBCL patients with c-MYC / Bcl-2 rearrangement have high-risk clinical characteristics and are prone to relapse and drug resistance. Even with high-intensity chemotherapy regimens, patients still fail to achieve a better prognosis. At present, there is no consensus on the best treatment for this type of lymphoma. At present, international research on this type of lymphoma has reached a bottleneck. How to discover new related pathways and drug-related targets and ultimately provide safe, effective and inexpensive drugs to the whole society is a problem of great significance to both basic and applied research in my country's biomedicine. Faced with the trend of increasing investment in new drug research and development for corresponding targets and increasing risk of failure year by year, exploring new indications for existing drugs (new uses of old drugs or repositioning of drugs) can effectively avoid research and development risks to a certain extent, reduce research and development costs, and speed up the pace of drug listing to quickly meet clinical drug needs. Therefore, it has become a strategy that many international pharmaceutical companies value and adopt.

[0006] "Comparative functional genomics" can break the analytical barriers that make it difficult to combine multi-omics data and realize the organic combination of "disease-gene-drug". By applying this method and clinical bioinformatics strategies, we can find compounds that have the potential to treat DLBCL with c-MYC / Bcl-2 rearrangement from many marketed compounds, greatly reducing the number of experimental screening compounds, saving financial and human resources, and achieving better treatment effects. There are currently no reports on the use of anastrozole in the treatment of lymphoma. Summary of the invention

[0007] According to one aspect of the present invention, an object of the present invention is to provide use of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a medicament for treating lymphoma.

[0008] Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

[0009] According to another aspect of the present invention, another object of the present invention is to provide a use of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof and an additional anticancer therapeutic agent in combination for preparing a medicament for treating lymphoma. The additional anticancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone and etoposide.

[0010] Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

[0011] According to another aspect of the present invention, another object of the present invention is to provide a use of a pharmaceutical composition in the preparation of a drug for treating lymphoma, wherein the pharmaceutical composition is composed of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient and a pharmaceutically acceptable excipient or carrier. Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

[0012] Preferably, the pharmaceutical composition comprises 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.

[0013] 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. Preferably, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, immediate-release dosage forms, sustained-release dosage forms, solutions or suspensions.

[0014] Preferably, the dosage of the pharmaceutical composition is determined according to the patient's age, condition, etc., and the unit dose of the formulation contains 0.05-200 mg of the anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof. Preferably, the unit dose of the formulation contains 1 mg-100 mg of the anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0015] Preferably, the dosage of the pharmaceutical composition is usually 0.001-100 mg / kg body weight per day, preferably 0.1-20 mg / kg body weight per day, taken once or in divided doses.

[0016] According to another aspect of the present invention, another object of the present invention is to provide a method for treating lymphoma, the method comprising administering to a patient a therapeutically effective amount of anastrozole or a pharmaceutically acceptable salt, solvate or hydrate thereof or the pharmaceutical composition. Preferably, the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0018] Figure 1 By analyzing the volcano plot of differential expression analysis of transcriptome sequencing data of GSE44164 double hit lymphoma patients, 835 differentially expressed genes were screened, including 521 up-regulated genes and 314 down-regulated genes. DETAILED DESCRIPTION

[0019] Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred examples for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0020] In this document, the terms "include", "including", "have", "contain" or any other similar terms are open conjunctions, which are intended to cover non-exclusive inclusions. For example, a composition or product containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or product. In addition, unless otherwise explicitly stated, the term "or" refers to an inclusive "or" rather than 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), and A and B are both true (or exist). In addition, in this document, the interpretation of the terms "include", "including", "have", and "contain" should be considered to have been specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as "consisting of" and "consisting essentially of".

[0021] In this article, all features or conditions defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values ​​within the range, especially integer values. For example, the range description of "1 to 8" should be deemed to have specifically disclosed all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., especially secondary ranges defined by all integer values, and should be deemed to have specifically disclosed individual values ​​such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise specified, the above interpretation method applies to all contents of the entire present invention, regardless of whether the range is broad or not.

[0022] If the 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 all ranges consisting of any upper limit or preferred value of the range and the lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, if a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0023] In this document, under the premise of achieving the purpose of the invention, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0024] definition

[0025] The term "pharmaceutically acceptable salt" refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and which are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. 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 amino salts formed 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 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, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4 alkyl)4-salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, when appropriate.

[0026] The term "solvate" refers to a compound form that is usually combined with a solvent by a solvolysis reaction. This physical combination can include hydrogen bonds. 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 solvates and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to separate. "Solvate" includes solution phase and separable solvates. Representative solvates include hydrates, ethanolates and methoxides.

[0027] The term "hydrate" refers to a compound that is combined with water. Typically, the number of water molecules contained in the hydrate of a compound is in a certain proportion to the number of molecules of the compound in the hydrate. Thus, a hydrate of a compound can, for example, be represented by the general formula R·xH2O, where R is a compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, such as a hemihydrate (R·0.5H2O)) and a polyhydrate (x is a number greater than 1, such as a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0028] As used herein, the term "treatment" refers to eliminating, alleviating or ameliorating a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith. As used herein, the term "treatment" and the like may include "preventive treatment," which refers to reducing the likelihood of redevelopment of a disease or condition or recurrence of a previously controlled disease or condition in a subject who is not or is at risk of developing or being susceptible to a disease or condition or recurrence of a disease or condition. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0029] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For example, for the oral dosage form 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 used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0030] 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 include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Pharmaceutically acceptable excipients that can be used to make the pharmaceutical compositions described herein include, but are not limited to, for example, inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents and flavoring agents may also be present in the composition.

[0031] The pharmaceutical composition can be formulated for any route of administration, such as oral administration. Typically, the pharmaceutical composition is a solid dosage form. However, in some embodiments, other dosage forms, such as liquids, suspensions, or semisolid dosage forms, can also be used.

[0032] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or (a) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid), (b) binders (e.g., carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia), (c) humectants (e.g., glycerol), (d) disintegrants (e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate), (e) retardants (e.g., paraffin), (f) absorption accelerators (e.g., quaternary ammonium compounds), (g) wetting agents (e.g., cetyl alcohol and glyceryl monostearate), (h) absorbents (e.g., kaolin and bentonite), and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0033] The term "subject", "patient" or "subject" refers to an animal, preferably a mammal, most preferably a human, that has been the object of treatment, observation or experiment. In any embodiment described herein, the subject can be a human.

[0034] The various dosage forms of the pharmaceutical composition disclosed herein 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.

[0035] The compounds and pharmaceutical compositions disclosed herein can be used clinically in mammals, including humans and animals, and can be administered by oral, nasal, skin, lung, or gastrointestinal tract administration. The best preferred daily dose is 0.1-20 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for the patient should be determined based on the specific treatment. Clinical trials usually start with a small dose and gradually increase the dose until the most suitable dose is found.

[0036] In common embodiments of the therapeutic methods provided by the present disclosure, the abnormal cell growth is cancer. The compounds of the present invention can be administered as a single agent or can be administered in combination with other anti-cancer therapeutic agents, particularly with standard of care agents applicable to the particular cancer.

[0037] The term "additional anticancer therapeutic agent" as used in the present disclosure refers to any one or more therapeutic agents other than the compounds of the present invention, which are used or can be used to treat lymphoma. In certain embodiments, such additional anticancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase 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 anticancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide.

[0038] In some embodiments, it is provided that the administration of the compounds of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

[0039] The pharmaceutical composition can be, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions; in a form suitable for parenteral injection, such as sterile solutions, suspensions or emulsions; in a form suitable for topical administration, such as ointments or creams; or in a form suitable for rectal administration, such as suppositories. Preferably, the form is tablets, capsules, pills, powders, immediate release formulations, sustained release formulations, solutions, suspensions.

[0040] The following examples are only listed as examples of embodiments of the present invention and do not constitute any limitation to the present invention. It can be understood by those skilled in the art that modifications within the scope of the essence and concept of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products.

[0041] Example

[0042] 1. Bioinformatics screening:

[0043] 1.1 Data sources and screening of differentially expressed genes

[0044] Data GSE44164 was screened from the Gene Expression Database (GEO), and 15 cases of high-grade B cell lymphoma (HGBCL) with Bcl-2 / c-MYC rearrangement of GBC subtype were selected as the experimental group, whose type was diffuse large B cell lymphoma (DLBCL); 13 cases of normal tonsil germinal center B cells were screened from the gene expression dataset GSE43677 of the same research group as the control group. Both dataset platforms were GPL96[HG-U133A]Affymetrix Human Genome U133A Array.

[0045] The obtained data and matrix were read and processed using R1.4.1717 software. After grouping, the obtained data set was screened for significantly differentially expressed genes using the limma3.49.4 software package, with a screening threshold of P < 0.05 and |log2FoldChange|> 0.5. The obtained differentially expressed genes (DEGs) were plotted using the ggplot2 software package.

[0046] Disease association analysis

[0047] 1.2 Drug Screening

[0048] Based on the theories of "system biology" and "comparative functional genomics", an "integrated multi-omics analysis" algorithm was designed. The disease or patient transcriptome and drug transcriptome were integrated and analyzed through the above data sources, and a clinical bioinformatics epigenomic precision medicine prediction platform (EpiMed) was established. The platform was used to perform correlation analysis between the above DEGs and drug transcriptome data, and to find drugs that can effectively treat monkeypox virus infection in humans among FDA-approved clinical drugs and traditional Chinese medicines. The screening conditions were correlation coefficient>|0.1|, P<0.05, and negatively correlated drugs were drugs with therapeutic effects.

[0049] 2. Experimental verification:

[0050] 2.1 Experimental Materials:

[0051] 2.1.1 Main reagents: PRIM 1640 culture medium (Gibco, USA), fetal bovine serum (Gibco, USA), penicillin-streptomycin-amphotericin (100X triple antibody) (Gibco, USA), CCK-8 kit (Dojindo, Japan), anastrozole (Shanghai Myrel Biochemical Technology Co., Ltd.)

[0052] 2.1.2 Main instruments: micropipette (2.5ul, 10ul, 20ul, 100ul, 200ul, 1000ul, 5000ul, Eppendorf, Germany), clean bench (Thermo Fisher, USA), cell culture incubator (Thermo Fisher, USA), microplate reader (Thermo Fisher, USA)

[0053] 2.1.3 Cell line: DOHH-2 (Bcl-2 / c-MYC rearranged diffuse large B-cell lymphoma cell line)

[0054] 2.2 Experimental methods:

[0055] 2.2.1 Preparation of complete cell culture medium: Take 6 ml of penicillin-streptomycin-amphotericin (100X triple antibody) and 56 ml of fetal bovine serum, add them to 500 ml of PRIM 1640 culture medium to prepare complete culture medium, and store it in a refrigerator at 4 degrees for future use.

[0056] 2.2.2 Cell culture and passaging: DOHH-2 cell lines were cultured with complete medium in a 37°C, 5% incubator.

[0057] 2.2.3 Drug preparation: Use an electronic balance to weigh a certain dose of the drug, dissolve the drug in DMSO, prepare a 10mmol / L solution, and store it at -30 degrees. When using, dilute the drug in the culture medium, and the prepared concentrations are 160umol / L, 120umol / L, 80umol / L, 40umol / L, and 20umol / L.

[0058] 2.2.4CCK-8 experiment: When the cell density reaches about 80%, the cell culture is carried out at a ratio of 1:3. After about 3 times of culture, the cells are cultured in serum-free medium for 24 hours, and the cells are selected for CCK-8 experiment. After centrifugation, the cells are resuspended in 10ml culture medium, 20ul of cells are added to 80ul of culture medium, and 10ul is added to the cell counting plate to calculate the total number of cells. Select the appropriate number of cells for the experiment. Inoculate 100ul of cell suspension in each well, and the number of cells in the well is about 5×10 4Each group has 3 replicate wells, and 100ul of drugs with different concentrations are added to each well to make the final concentration in the well 80umol / L, 60umol / L, 40umol / L, 20umol / L, and 10umol / L. 100ulPBS is added to the outermost part of the 96-well plate. At three time points (24h, 48h, and 72h), 20ulCCK-8 solution (CCK-8 solution concentration in each well is 10%) is added to each well, shaken and incubated in the incubator for 2h, and then the OD value of each well at a wavelength of 450nm is read on an enzyme reader and the data is recorded.

[0059] 2.2.5 The drug killing inhibition rate was calculated as follows: drug killing inhibition rate (%) = 1-(mean OD of experimental group-blank OD) / (mean OD of control group-blank OD)×100%.

[0060] 2.2.6 Statistical method: Three independent experiments were performed and the results were averaged.

[0061] 3. Bioinformatics screening results

[0062] 3.1 Results of differentially expressed gene screening

[0063] By analyzing the transcriptome sequencing data of GSE44164 double-hit lymphoma patients, 835 differentially expressed genes were screened out ( Figure 1 , volcano plot of differential expression analysis), among which 521 genes were up-regulated and 314 were down-regulated.

[0064] 3.2 Prediction results of differentially expressed genes and drugs

[0065] The above 835 differentially expressed genes were imported into EpiMed and integrated with the disease or patient transcriptome and drug transcriptome for analysis. Drugs that can effectively treat this type of lymphoma were sought among FDA-approved clinical drugs and traditional Chinese medicines. The screening criteria were correlation coefficient >|0.1|, P<0.05. Negatively correlated drugs were those with therapeutic effects, and anastrozole was screened out as a potential therapeutic drug.

[0066] 4. Experimental verification of the drug's killing effect on lymphoma cells

[0067] 4.1 The prediction results of differentially expressed genes and drugs are shown in Table 2.

[0068] Table 2

[0069] Day 1 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％ Day 3 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％

[0070] Inhibition rate 1, inhibition rate 2, and inhibition rate 3 were repeated three times in parallel, and the final results were averaged. After 24h, 48h, and 72h of anastrozole action, as the concentration of anastrozole increased, the inhibition of lymphoma cell proliferation gradually increased, and its half-inhibitory concentration was about 40umol / L, with a considerable inhibitory effect.

[0071] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. Use of anastrozole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lymphoma, wherein the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

2. Use of anastrozole or a pharmaceutically acceptable salt thereof and an additional anticancer therapeutic agent in combination for preparing a medicament for treating lymphoma, wherein the additional anticancer therapeutic agent is selected from one or more of cyclophosphamide, vincristine, doxorubicin, prednisone, and etoposide, and the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

3. Use of a pharmaceutical composition in the preparation of a drug for treating lymphoma, the pharmaceutical composition consisting of anastrozole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier as an active ingredient, wherein the lymphoma is diffuse large B-cell lymphoma with c-MYC rearrangement.

4. The use according to claim 3, characterized in that The pharmaceutical composition comprises 1-99 wt % of anastrozole or a pharmaceutically acceptable salt thereof and 1-99 wt % of a pharmaceutically acceptable excipient or carrier.

5. The use according to claim 3, characterized in that: The pharmaceutical composition is prepared into tablets, capsules, pills, powders, immediate-release dosage forms, sustained-release dosage forms, solutions, suspensions, emulsions, ointments or suppositories.

6. The use according to claim 5, characterized in that The pharmaceutical composition is in the form of tablets, capsules, pills, powders, immediate-release dosage forms, sustained-release dosage forms, solutions or suspensions.

7. The use according to claim 3, characterized in that: The dosage of the pharmaceutical composition is determined according to the age and condition of the patient, and the unit dose of the formulation contains 0.05-200 mg of the anastrozole or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, characterized in that The unit dose of the formulation contains 1 mg to 100 mg of the anastrozole or a pharmaceutically acceptable salt thereof.

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