CN117243963A - Application of Remodelin and Venetoclax in treating cancer - Google Patents

Application of Remodelin and Venetoclax in treating cancer Download PDF

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Publication number
CN117243963A
CN117243963A CN202311177138.4A CN202311177138A CN117243963A CN 117243963 A CN117243963 A CN 117243963A CN 202311177138 A CN202311177138 A CN 202311177138A CN 117243963 A CN117243963 A CN 117243963A
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cancer
carcinoma
remodelin
venetoclax
aml
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周景峰
李舒宜
苏永伟
王蕾
陈菁鸿
于力
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Shenzhen University General Hospital
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Shenzhen University General Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0693—Tumour cells; Cancer cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components

Abstract

The invention belongs to the field of medicines, and particularly relates to application of Remodelin and Venetoclax in treating cancers. The invention provides application of venetoclax and Remodelin in preparing medicines for treating cancers. In vivo and in vitro experiments prove that the combined administration can inhibit the activity and proliferation of cancer cells, and the animal experiments show that the combination of the two medicines can obviously prolong the survival time of mice, relieve splenomegaly and reduce abnormal primitive cells.

Description

Application of Remodelin and Venetoclax in treating cancer
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of Remodelin and Venetoclax in treating cancers.
Background
Leukemia is one of ten major malignant tumors in China, and acute myelogenous leukemia (Acute myeloid leukemia, AML) has the advantages of large heterogeneity, complex pathogenesis, rapid progress, high recurrence drug resistance rate, high treatment cost and great economic burden to families and society.
AML is a heterogeneous disease, AML cells of different patients possess different combinations of mutant genes, such as point mutations of IDH1, TET2, NPM1, CEBPA and RUNX1, and a series of chromosomal Structural Variations (SV), such as inv (3), inv (16), t (8; 21), t (9; 22) and t (6; 9), etc. Chromosomal translocation is the most common genetic abnormality of AML, and the resulting fusion gene is often an important driver for AML occurrence and progression. Wherein T (8; 21) (q 22; q 22) is the most common type of chromosomal translocation in clinic, i.e., translocation results in fusion of the ETO gene located on chromosome 8 with the AML1 gene located on chromosome 21, forming an AML1-ETO fusion gene (also known as RUNX1-RUNX1T1 fusion gene), whose expressed and produced proteins affect normal differentiation of hematopoietic stem cells via various pathways, resulting in arrest of myeloid differentiation, resulting in the occurrence of leukemia. t (8; 21) AML accounts for 12-15% of all AMLs, and up to 40% -60% of M2 type AMLs. t (8; 21) AML prognosis is good, with overall remission rates as high as 60%.
Nevertheless, the long-term survival rate caused by high drug resistance and recurrence rate is still a difficult problem faced by clinic, and the survival rate of 3 years is less than 35.5% according to the data monitored by the national cancer institute. At its root, the presence of leukemia stem cells (leukemia stem cell, LSCs) is the source of AML drug-resistant recurrence. However, the regulatory mechanism of t (8; 21) AML leukemia stem cells is not completely elucidated, the regulatory mechanism of stem cell function maintenance is explored, the mechanism of t (8; 21) AML drug resistance relapse and treatment difficulty is deeply recognized, and new means and strategies are provided for clinical diagnosis and treatment.
Venetoclax (ABT-199), a novel Bcl-2 selective inhibitor, also known as Venetoclax, veneturacrat, can be used in combination with azacitidine, decitabine, or low dose cytarabine to treat AML patients over 75 years old. Although valnemulin demonstrated good clinical efficacy, some AML patients developed relapse, resistance to drugs, and eventually died after treatment with valnemulin. The drug has natural drug resistance or acquired drug resistance to the valnemulin, which is a great obstacle for treating AML by clinically applying the valnemulin. Therefore, further discussing the drug resistance mechanism of valnemulin, finding a novel therapeutic strategy to enhance the anti-AML activity of valnemulin has particular importance and urgency for improving the cure rate of AML.
Disclosure of Invention
The invention provides the combination administration of venetoclax and remodelin for the first time to treat cancer, and in vivo and in vitro experiments prove that the combination administration can inhibit the activity and proliferation of cancer cells, and the combination of the two medicines can obviously prolong the survival time of mice, relieve splenomegaly and reduce abnormal primitive cells in animal experiments.
Specifically, the invention provides the following technical scheme:
in a first aspect, the present invention provides a pharmaceutical combination composition having the effect of preventing, alleviating and treating cancer, comprising: 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof.
Preferably, the pharmaceutical combination composition further comprises pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise any one or a combination of at least two of diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostats or buffers.
The dosage form and the mode of administration of the pharmaceutical combination composition of the present invention are not particularly limited. Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.
In a specific embodiment, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
In a specific embodiment, the liquid dosage form for oral administration comprises a pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Such as suspensions, may contain suspending agents as, for example, particularly ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
In a particular embodiment, a composition for parenteral injection may comprise a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
In a specific embodiment, the dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. Is prepared by mixing the active ingredient under aseptic condition with pharmaceutically acceptable carrier and any preservative, buffer or propellant as required.
Preferably, the pharmaceutical combination composition may be administered orally.
Preferably, the dosage form of the pharmaceutical combination composition comprises a capsule, a tablet, a pill, a powder, a granule, an emulsion, a solution, a suspension, a syrup or a tincture.
In a specific embodiment, the dosage forms of 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof in the pharmaceutical combination composition are the same or different.
In a specific embodiment, 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof are administered simultaneously or sequentially, in particular, may be administered at intervals of 0, 1, 2, 3, 4, 5, 6, 7 or more days.
In a specific embodiment, the dosage ratio of 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof in the pharmaceutical combination composition is 1:0.1-2; specifically included are 3:1, 2:1, 1:1, 1:2, 1:3.
Preferably, the mass ratio of the two main active ingredients in the pharmaceutical combination composition is 1:1.
Most preferably, the effective dose of vennetoclax is 100-600 mg/day.
Most preferably, the effective dose of Remodelin is 100-600 mg/day.
Preferably, other cancer drugs such as doxorubicin, vincristine, vinorelbine, paclitaxel, cisplatin, actinomycin, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, epirubicin, etoposide, podophyllotoxin, etoposide, and the like may also be included in the pharmaceutical combination composition.
In another aspect, the invention provides the use of venetoclax and Remodelin in the manufacture of a medicament for the treatment of cancer.
In particular, the manifestations of treating cancer include prolonged survival, remission of splenomegaly, and abnormal primordial cytopenia.
Preferably, vennetoclax and Remodelin are administered simultaneously or sequentially;
preferably, the venetoclax and Remodelin may also be used in combination with other anticancer drugs and cancer treatments.
Specifically, the other anticancer drugs are exemplified by doxorubicin, vincristine, vinorelbine, taxol, cisplatin, actinomycin, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, epirubicin, etoposide, podophyllotoxin, fluoroarabinoic acid, and the like. Other cancer treatment modalities such as: chemotherapy, radiation therapy, immunotherapy, gene therapy, surgery, etc.
As is well known to those skilled in the art, the effective dosages (administration dosages) of the venetoclax and the Remodelin vary depending on the route of administration, the use of excipients, and co-administration with other therapeutic modalities.
In another aspect, the invention provides the use of Remodelin in the manufacture of a product for the treatment of cancer, reducing the toxic side effects of venetoclax.
In another aspect, the invention also provides a method of treating cancer comprising administering to a cancer patient Remodelin and vennetoclax.
Examples of cancers described herein include, but are not limited to, cervical cancer, seminoma, testicular lymphoma, prostate cancer, ovarian cancer, lung cancer (e.g., small cell lung cancer SCLC, non-small cell lung cancer NSCLC, lung adenocarcinoma), rectal cancer, breast cancer, cutaneous squamous cell carcinoma, colon cancer, liver cancer, pancreatic cancer, esophageal cancer, thyroid cancer, transitional bladder epithelial cancer, leukemia (e.g., acute lymphoblastic leukemia ALL, acute myelogenous leukemia AML, chronic myelogenous leukemia CML, chronic lymphocytic leukemia CLL), brain tumor, gastric cancer, peritoneal cancer, head and neck cancer, endometrial cancer, kidney cancer, female genital tract cancer, carcinoma in situ, neurofibromatosis, bone cancer, skin cancer, gastrointestinal stromal tumors, mast cell tumors, multiple myeloma, melanoma, glioma.
Preferably, the cancer of the invention is an Acute Myeloid Leukemia (AML), a group of malignant clonal diseases of hematopoietic tissue origin characterized by abnormal primitive cell accumulation and by a disorder of normal blood cell production and differentiation.
Preferably, the cancer is acute myelogenous leukemia AML.
Preferably, the cancer is AML of the following subtype: inv (3), inv (16), t (8; 21), t (9; 22) and t (6; 9).
More preferably, the cancer is AML of subtype t (8; 21), i.e. with 8: chromosome 21-translocated AML.
More preferably, the AML comprises relapsed AML, refractory AML.
The term "Venetoclax (Venetatora, venetatox, van. Toxox, ABT-199, GDC-0199)" as used herein is the first small molecule inhibitor against protein-protein interactions (PPI) worldwide, and is a highly potent, selective and orally active small molecule Bcl-2 inhibitor that binds to the hydrophobic groove of Bcl-2, disrupting the interaction of the Bcl-2 molecule with pro-apoptotic proteins (e.g., bax). The Venetoclax comprises Venetoclax pharmaceutically acceptable salts.
The term "Remodelin (Histone Acetyltransferase inhibitor)" as used herein is known under the chemical name 4- (N, N-dimethylamino) azobenzene-4' -isothiocyanate, and is a known potent acetate-transferase NAT10 inhibitor. The Remodelin disclosed by the invention comprises a pharmaceutically acceptable salt of Remodelin.
In another aspect, the invention provides a method of inhibiting cell viability of AML cells comprising the step of administering venetoclax and Remodelin.
Preferably, the method is non-therapeutic.
More specifically, the AML cells include Kasumi-1, SKNO-1 or cells from AML patients.
The beneficial effects are that:
the mode of combined administration of the venetoclax and the Remodelin provided by the invention not only reduces the dosage of the venetoclax and reduces toxic and side effects, but also achieves the effect of cooperative treatment.
Drawings
FIG. 1 is a result of verifying the synergistic effect of vennoclax and Remodelin in Kasumi-1 cells.
FIG. 2 is a result of verifying the synergistic effect of vennoclax and Remodelin in SKNO-1 cells.
FIG. 3 is a result of verifying the synergistic effect of vennoclax and Remodelin in AML clinical sample cells.
Fig. 4 is a representative view of the spleen of mice after drug treatment.
Fig. 5 is a graph of the statistical results of spleen weights after drug treatment.
FIG. 6 is a graph of statistical results of leukemia cell numbers in mouse bone marrow using flow assays.
Fig. 7 is a graph of survival of AML mice after treatment.
FIG. 8 is a graph of Giemsa staining results of peripheral blood smears of mouse tails.
FIG. 9 is a graph of HE staining results.
Detailed Description
The present invention is further described in terms of the following examples, which are given by way of illustration only, and not by way of limitation, of the present invention, and any person skilled in the art may make any modifications to the equivalent examples using the teachings disclosed above. Any simple modification or equivalent variation of the following embodiments according to the technical substance of the present invention falls within the scope of the present invention.
Example 1 determination of the Combined Effect of two drugs Using the MTS method
The operation steps are as follows:
counting cells, ensuring that the cell viability is greater than 95%, and adjusting the cell concentration to 4×10 with culture medium 5 /ml. Volume per well: 50 μl, i.e. cell number per well: 2X 10 4 And each.
According to the solubility of the medicine, remodelin is subjected to multiple ratio dilution by using RPMI-1640 culture medium, and the final concentration is 0, 1.25, 2.5, 5, 10, 20 and 40 mu M; venetoclax was also subjected to multiple dilution, with Kasumi-1 cells set at 0, 12.5, 25, 50, 100, 200nM and SKNO-1 set at 0, 0.5, 1, 2, 4, 8. Mu.M due to the different sensitivity of the cells to the drug.
Mu.l of the drugs Venetoclax and Remodelin were added to the corresponding wells of the 96-well plate, respectively, to make the total volume 100. Mu.l. 4 secondary wells were provided for each concentration. Single drug wells were supplemented with 25. Mu.LRPMI-1640 medium and control wells were supplemented with 50. Mu.L medium.
The culture was performed at 37℃for 68 hours in an incubator, and 10. Mu.L of MTS mixture (MTS: PMS=20:1) was added thereto, followed by treatment for 4 hours. Reading OD with an ELISA reader 490 Values.
Calculation of IC with GraphPad Prism software 50 Values (drug concentration at which 50% inhibition is achieved for cells) and standard isobolograms were made to evaluate the combined effect of the two drugs.
Experimental results:
the results are shown in fig. 1-2, with the dots in the graph representing: IC50 values of Remodelin at a concentration of venetoclax. In the figure, a point falling below the oblique line represents that the two-medicine combination has a synergistic effect, a point falling on the oblique line represents that the two-medicine combination has a superposition effect, and a point falling outside the oblique line represents that the two-medicine combination has an antagonistic effect. The result shows that the combination of the Remodelin and the Venetoclax can synergistically inhibit the activity of AML cells, and the combination of the two medicines has synergistic anti-AML activity.
Example 2, validation of synergistic effects of vennoclax and Remodelin in AML clinical sample cells
The operation steps are as follows:
counting cells, ensuring that the cell viability is greater than 95%, and adjusting the cell concentration to 2×10 with culture medium 6 Per ml,500 μl system. Are arranged into 4 groups, and are divided into a combination group of vehicle, remodelin, venetoclax, remodelin and Venetoclax.
The final concentration was adjusted to 10. Mu.M by adding Remodelin, 200nM by adding Venetoclax, and the cells in the well plate were thoroughly mixed with the drug.
After 24h of drug action, counting was started. The effect of the combination of the two drugs on AML cell proliferation was assessed by counting with trypan blue dye for 7 consecutive days and using GraphPad Prism software statistics.
Experimental results:
the results are shown in FIG. 3, where the dots represent the number of cells counted daily and the cell proliferation capacity was measured by continuous 7 day counting using trypan blue after administration of both Remodelin and Venetoclax drugs in the t (8; 21) AML samples. * P <0.05, < P <0.01, < P <0.001; one-way ANOVA, post hoc comparisons, tukey's test. This part of the results shows that the combination of Remodelin and Venetoclax can synergistically inhibit the proliferation of AML cells, and the effect is superior to that of single medicine.
Example 3 validation of synergistic effects of vennoclax and Remodelin in animal models
Preparing the medicine:
remodelin: working solution concentration 10mg/ml, formula: 20%DMSO+65%PEG300+15%TWEEN 80; preparing 50mg/ml mother liquor, dissolving 400mg of medicine in 8000 μl DMSO solution, subpackaging into 800 μl/branch, freezing at-80deg.C, adding 2600 μl PEG300 into 800 μl DMSO mother liquor, clarifying, adding 600 μl TWEEN80, and mixing.
Venetoclax: working solution concentration 10mg/ml, formula: 5% DMSO+50% PEG300+5% TWEEN80+40% ddH 2 O; preparing 200mg/ml mother liquor, dissolving 400mg of medicine in 2000 μl DMSO solution, packaging into 200 μl/branch, freezing at-80deg.C, collecting 200 μl DMSO mother liquor when in use, adding 2000 μl PEG300, clarifying, adding 200 μl TWEEN80, mixing, and adding 1600 μl dDH 2 O can be used.
The operation steps are as follows:
3C 57BL/6J male mice with the age of 6-8 weeks and the weight of 18-22g were taken, 6 female mice were checked after overnight mating, female mice were sacrificed after 14.5 days for fetal liver cells, cells were infected 2 times with MSCV-AML-ETO9a-IRES-tNGFR retrovirus (AML 1-ETO9a isomer is a fusion gene leading to the occurrence of t (8; 21) AML), erythrocytes were lysed, and cells were counted 1X 10 6 In each case, the tail vein was injected into 750cGy irradiated recipient mice.
After waiting 21 days for leukemia to occur in the mice, the mice were euthanized, spleen and bone marrow cells were taken, and cells were counted 1×10 6 Cells were transplanted into 450cGy irradiated recipient mice.
Mice were divided into 4 groups, respectively, vehicle, remodelin, vennoclax, the combination of Remodelin and vennoclax, 6 groups. The following day treatment by gavage was started with 100mg/kg of Remodelin and 100mg/kg of Venetoclax for 14 consecutive days. After euthanasia of half of the mice, the mice were dissected, bone marrow and spleen cells were harvested, flow stained, and HE stained for spleen changes. The other half of the mice continued to be carefully attended to and the mice were monitored for survival.
Experimental results:
fig. 4: spleen representative of mice after drug treatment. Fig. 5: spleen weight after drug treatment. Fig. 6: leukemia cells in mouse bone marrow were detected using flow-through. Fig. 7: after treatment, continuous observation was performed to count survival of AML mice. Survival graph 8 was plotted with Kaplan-Merier: peripheral blood smears were taken from the mouse tails, giemsa stained, and primordial cell ratios were observed. Fig. 9: HE staining observed spleen lesions. * P <0.05, < P <0.01, < P <0.001.
The results in this section show that the survival time of mice is prolonged after the combination treatment of the two drugs, and leukemia cells in bone marrow are reduced. Peripheral blood smears were seen with primitive granulocytes, promyelocytes in the Vehicle and Venetoclax groups, and mature granulocytes in the remodelin and co-administered groups. Both drugs can relieve splenomegaly of AML mice, reduce lesions and have better combined effect.

Claims (10)

1. A pharmaceutical combination composition having the function of preventing, alleviating and treating cancer, comprising: 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof.
2. The pharmaceutical combination composition of claim 1, wherein the dosage ratio of 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof is 1:0.1-2;
preferably, the dose ratio comprises 3:1, 2:1, 1:1, 1:2, 1:3;
preferably, the dose ratio is 1:1.
3. The pharmaceutical combination composition of claim 1, further comprising pharmaceutically acceptable excipients comprising any one or a combination of at least two of diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, co-solvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostats or buffers.
4. The pharmaceutical combination composition of claim 1, which is administered orally, nasally, intravenously, intra-arterially, intradermally, subcutaneously, intramuscularly, intraperitoneally, intrapleurally, intravaginally, intraurethrally, intratumorally, intracranially, intrathecally;
preferably, the dosage form of the pharmaceutical combination composition comprises a capsule, a tablet, a pill, a powder, a granule, an emulsion, a solution, a suspension, a syrup or a tincture;
preferably, the dosage forms of 1) venetoclax and pharmaceutically acceptable salts thereof, and 2) Remodelin and pharmaceutically acceptable salts thereof in the pharmaceutical combination composition are the same or different;
preferably, the pharmaceutical combination composition further comprises any one or more of the following: doxorubicin, vincristine, vinorelbine, taxol, cisplatin, actinomycin, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, epirubicin, etoposide, fluoroarabinoic acid.
Use of vennetoclax and Remodelin in the manufacture of a medicament for the treatment of cancer;
preferably, the manifestations of treating cancer include prolonged survival, remission of splenomegaly and abnormal primordial cytopenia;
preferably, the vennetoclax and Remodelin are administered simultaneously or sequentially;
preferably, the dose ratio of the vennetoclax to the Remodelin is 1:0.1-2;
preferably, the dose ratio comprises 3:1, 2:1, 1:1, 1:2, 1:3;
preferably, the dose ratio is 1:1.
6. The use of claim 5, wherein the cancer comprises melanoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial carcinoma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyoma, ependymoma, pineal tumor, angioblastoma, auditory glioma, oligodendroglioma, meningioma, neuroblastoma, gastric cancer, retinoblastoma, gastric cancer, and anterior carcinoma;
preferably, the cancer is acute myelogenous leukemia;
preferably, the cancer is AML of the following subtype: inv (3), inv (16), t (8; 21), t (9; 22) and t (6; 9);
more preferably, the cancer is AML of subtype t (8; 21).
7. The use of claim 5, wherein the vennetoclax and Remodelin are each independently administered orally, nasally, intravenously, intraarterially, intradermally, subcutaneously, intramuscularly, intraperitoneally, intrapleurally, intravaginally, intraurethrally, intratumorally, intracranially, intrathecally;
preferably, the formulations of venetoclax and Remodelin, each independently, comprise capsules, tablets, pills, powders, granules, emulsions, solutions, suspensions, syrups or tinctures.
8. The use of claim 5, wherein the venetoclax and Remodelin are used in combination with other anticancer agents and cancer treatment modalities;
preferably, the other anticancer drug comprises doxorubicin, vincristine, vinorelbine, paclitaxel, cisplatin, actinomycin, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, epirubicin, etoposide, podophyllotoxin, fluoroarabinoic acid;
preferably, other cancer treatment modalities include chemotherapy, radiation therapy, immunotherapy, gene therapy, surgery.
Application of remodelin in preparation of products for treating cancers and reducing toxic and side effects of venetoclax;
preferably, the cancer comprises melanoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelioma, synovial carcinoma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchi carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, neuroblastoma, craniopharyngema, ventricular omeningioma, pineal tumor, angioblastoma, auditory glioma, oligodendroglioma, meningioma, neuroblastoma, gastric carcinoma, gastric cancer, and anterior carcinoma;
preferably, the cancer is acute myelogenous leukemia;
preferably, the cancer is AML of the following subtype: inv (3), inv (16), t (8; 21), t (9; 22) and t (6; 9);
more preferably, the cancer is AML of subtype t (8; 21).
10. A method of inhibiting cell viability of AML cells, the method comprising the step of administering venetoclax and Remodelin, the method being non-therapeutic;
more preferably, the AML cells comprise Kasumi-1, SKNO-1 or cells from an AML patient.
CN202311177138.4A 2023-09-13 2023-09-13 Application of Remodelin and Venetoclax in treating cancer Pending CN117243963A (en)

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