WO2023035200A1 - Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre - Google Patents

Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre Download PDF

Info

Publication number
WO2023035200A1
WO2023035200A1 PCT/CN2021/117534 CN2021117534W WO2023035200A1 WO 2023035200 A1 WO2023035200 A1 WO 2023035200A1 CN 2021117534 W CN2021117534 W CN 2021117534W WO 2023035200 A1 WO2023035200 A1 WO 2023035200A1
Authority
WO
WIPO (PCT)
Prior art keywords
endometrial cancer
cells
penfluridol
active ingredient
kle
Prior art date
Application number
PCT/CN2021/117534
Other languages
English (en)
Chinese (zh)
Inventor
王玉东
毛斐
伍慧雯
孙笑
刘小虎
李丽娟
沈鑫龙
李剑
李晓康
朱进
Original Assignee
中国福利会国际和平妇幼保健院
华东理工大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国福利会国际和平妇幼保健院, 华东理工大学 filed Critical 中国福利会国际和平妇幼保健院
Priority to CN202180100160.1A priority Critical patent/CN117642164A/zh
Priority to PCT/CN2021/117534 priority patent/WO2023035200A1/fr
Publication of WO2023035200A1 publication Critical patent/WO2023035200A1/fr

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the technical field of medicines, and in particular relates to the application of penfluridol in the preparation of medicines for treating endometrial cancer.
  • Endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium. It is one of the most common gynecological malignancies in the world, and its morbidity and mortality are increasing. Although EC is more common in postmenopausal women, the incidence of EC in young women has increased dramatically over the past decade, with younger and younger women being diagnosed with endometrial cancer, and the underlying cause of the increase is obesity The prevalence and resulting hyperinsulinemia, and endometrial cancer rates have risen along with obesity rates. In 2015, there were about 63,400 new EC cases and about 21,800 new EC deaths in China.
  • EC is usually divided into type I and type II.
  • type I EC is positive for progesterone receptor expression
  • type II EC is negative for progesterone receptor expression.
  • surgical treatment is a common method for the treatment of EC, but conservative treatment with progesterone therapy is required for patients who need to protect their reproductive function, and the main method of conservative treatment is hormone therapy with progesterone drugs.
  • hormone therapy has limitations. It is only effective for patients with positive progesterone receptor expression and has a high recurrence rate, which is prone to drug resistance.
  • the purpose of the present invention is to provide a drug capable of treating endometrial cancer, especially progesterone receptor-negative and progesterone-resistant EC.
  • an active ingredient or a preparation containing the active ingredient in the preparation of a drug for treating and/or preventing endometrial cancer wherein the active ingredient is penfluridol or its Pharmaceutically acceptable salts.
  • the present invention also provides an active ingredient or a preparation containing the active ingredient for treating and/or preventing endometrial cancer, wherein the active ingredient is penfluridol or a pharmaceutically acceptable salt thereof.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the endometrial cancer includes progesterone-sensitive endometrial cancer or progesterone-resistant endometrial cancer.
  • the endometrial cancer is progesterone receptor-negative and progesterone-resistant endometrial cancer.
  • the active ingredient or the preparation containing the active ingredient is used to prepare medicines for one or more of the following purposes:
  • the endometrial cancer cells are selected from the group consisting of ISK, KLE, HEC-1-A, HEC-1-B and AN3CA or combinations thereof.
  • the endometrial cancer cells are ISK and/or KLE cells.
  • the preparation is an oral preparation or a non-oral preparation.
  • the preparation is selected from the group consisting of injection, inhalation, tincture, powder, granule, capsule, oral liquid, tablet, pill, suspension, emulsion, lozenge, or drop pill.
  • the administration of the preparation is oral or injection.
  • the preparation further includes other anti-endometrial cancer drugs.
  • the anti-endometrial cancer drug is progesterone.
  • the progestin is selected from: megestrol acetate, medroxyprogesterone acid, progesterone caproate, or combinations thereof.
  • the other anti-endometrial cancer drug is medroxyprogesterone acid.
  • composition which comprises:
  • the anti-endometrial cancer drug is progesterone.
  • the progestin is selected from: megestrol acetate, medroxyprogesterone acid, progesterone caproate, or combinations thereof.
  • the other anti-endometrial cancer drug is medroxyprogesterone acid.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the first active ingredient accounts for 0.1-99% by mass of the total weight of the drug.
  • a method for inhibiting endometrial cancer cells in vitro comprising the steps of:
  • the method is non-therapeutic and non-diagnostic.
  • the inhibition is selected from the group:
  • the endometrial cancer cells are selected from the group consisting of ISK, KLE, HEC-1-A, HEC-1-B and AN3CA or combinations thereof.
  • the endometrial cancer cells are ISK and/or KLE cells.
  • a method for treating endometrial cancer comprising the step of administering to a subject in need a therapeutically effective amount of penfluridol or a pharmaceutically acceptable salt thereof or the second aspect of the present invention
  • the pharmaceutical composition comprising the step of administering to a subject in need a therapeutically effective amount of penfluridol or a pharmaceutically acceptable salt thereof or the second aspect of the present invention
  • the pharmaceutical composition comprising the step of administering to a subject in need a therapeutically effective amount of penfluridol or a pharmaceutically acceptable salt thereof or the second aspect of the present invention.
  • the subject is a patient with endometrial cancer.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • Fig. 1 is a schematic diagram of the proliferation inhibitory activity of penfluridol on ISK and KLE cells after acting on them for different periods of time.
  • A ISK cell proliferation inhibitory activity
  • B KLE cell proliferation inhibitory activity.
  • Figure 2 is a schematic diagram of the effect of penfluridol on the clone formation of ISK and KLE cells.
  • A ISK cell crystal violet staining
  • B ISK cell crystal violet staining quantification
  • C KLE cell crystal violet staining
  • D KLE cell crystal violet staining quantification.
  • Figure 3 is a schematic diagram of the effect of penfluridol on the migration ability of ISK and KLE cells.
  • A ISK cell crystal violet staining
  • B ISK cell crystal violet staining quantification
  • C KLE cell crystal violet staining
  • D KLE cell crystal violet staining quantification.
  • Fig. 4 is a schematic diagram showing the effect of penfluridol on the apoptosis of ISK and KLE cells.
  • A Effect of penfluridol on apoptosis of ISK cells;
  • B Effect of penfluridol on apoptosis of KLE cells;
  • C Quantification of apoptosis ratio of ISK cells;
  • D Quantification of apoptosis ratio of KLE cells.
  • Figure 5 shows the inhibitory effect of penfluridol on the growth of subcutaneous KLE cell transplanted tumors in mice.
  • A Change curve of mouse body weight with administration time;
  • B Tumor volume after administration for 14 days;
  • C Tumor pictures of mice after administration for 14 days;
  • D Tumor weight after administration for 14 days.
  • the inventor unexpectedly discovered a new application of the antipsychotic drug penfluridol in the preparation of a drug for treating endometrial cancer.
  • the inventors found through experiments that penfluridol has inhibitory effects on the proliferation, clone formation and migration of endometrial cancer ISK and KLE cells, and can induce apoptosis of EC cells.
  • Experiments in mice showed that penfluridol can inhibit the growth of subcutaneous transplanted tumors in mice. On this basis, the present invention has been accomplished.
  • the terms “comprising”, “including”, and “containing” are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • pharmaceutically acceptable carrier refers to ingredients suitable for humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic reactions), that is, with a reasonable benefit/risk ratio substance.
  • the term "therapeutically effective amount” refers to an amount that produces functions or activities on humans and/or animals and is acceptable to humans and/or animals. Those of ordinary skill in the art should understand that the “therapeutically effective amount” may vary depending on the form of the pharmaceutical composition, the route of administration, the adjuvant of the drug used, the severity of the disease, and the combination with other drugs. different.
  • PFL Penfluridol
  • active ingredient of the present invention active ingredient of the present invention
  • compound of the present invention is used interchangeably, and all refer to penfluridol and its pharmaceutically acceptable salts.
  • the penfluridol has the following structural formula:
  • Penfluridol is an oral long-acting antipsychotic drug approved by the U.S. Food and Drug Administration (FDA). For the treatment of various types of schizophrenia. Penfluridol is a potent inhibitor of dopamine D2 receptors and calcium channels.
  • penfluridol has a proliferation inhibitory effect on endometrial cancer cell ISK (type I, progesterone-sensitive), and further research found that it has an inhibitory effect on type II endometrial cancer cell KLE (progesterone-sensitive type).
  • Drug-resistant type has an inhibitory effect on proliferation, can inhibit the formation and migration of two EC cell clones, induce EC cell apoptosis, and can inhibit the growth of subcutaneous xenograft tumors in nude mice in vivo. Therefore, the penfluridol of the present invention can be applied to the preparation of medicines for treating endometrial cancer.
  • endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium, also known as uterine body cancer, and is one of the three most common malignant tumors of the female reproductive system. . Endometrial cancer is more likely to occur in perimenopausal and postmenopausal women. According to its pathogenesis and biological behavior characteristics, it can be divided into type I endometrial cancer (estrogen-dependent type) and type II endometrial cancer (non-estrogen-dependent type). hormone-dependent).
  • the present invention also provides a pharmaceutical composition capable of effectively treating endometrial cancer, comprising:
  • the anti-endometrial cancer drug is progesterone.
  • the progesterone is selected from: megestrol acetate (MA), medroxyprogesterone acetate (MPA), progesterone caproate (HPC), or a combination thereof.
  • the other anti-endometrial cancer drug is MPA.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the pharmaceutical composition provided by the present invention preferably contains the first active ingredient in a weight ratio of 0.1-99wt%, and the rest is the second active ingredient, pharmaceutically acceptable carrier, diluent or solution or saline solution.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, injections, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or Diluent and appropriate sterile equipment for injection or infusion.
  • the unit dose of the preparation formula usually contains 0.05-1000 mg of the active compound of the present invention, preferably, the unit dose of the preparation formula contains 1 mg-500 mg of the active compound of the present invention.
  • the pharmaceutical composition of the present invention can be clinically used in mammals, including humans and animals, and can be administered through oral, nasal, skin, lung or gastrointestinal tract and other routes. Oral administration is most preferred.
  • the most preferred daily dose is 0.01-400 mg/kg body weight, taken once, or 0.01-200 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual should depend on the specific treatment. Usually, start with a small dose and gradually increase the dose until you find the most suitable dose.
  • the drug or inhibitor of the present invention can be administered in various ways, for example, it can be introduced into the body by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemically mediated methods such as muscle, intradermal, subcutaneous, intravenous , mucosal tissue; or mixed or wrapped by other substances into the body.
  • the active ingredient of the present invention or the pharmaceutical composition containing it can be administered in unit dose form, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, Eyes, lungs and respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage form can be solution (including true solution and colloid solution), emulsion (including O/W type, W/O type and double emulsion), suspension, injection (including water injection, powder injection and infusion), eye drops Agents, nasal drops, lotions and liniments, etc.
  • solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.
  • semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the active ingredients of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, Isopropanol, etc.
  • binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrants can be dry starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, Isopropanol, etc.
  • binders can be starch
  • Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • the active ingredient of the present invention can be mixed with a diluent and a glidant, and the mixture is directly placed in a hard capsule or a soft capsule.
  • the active ingredients can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard or soft capsules.
  • Various diluents, binders, wetting agents, disintegrants, and glidants that are used to prepare the tablet of the present invention can also be used to prepare the capsule of the present invention.
  • water, ethanol, isopropanol, propylene glycol or their mixture can be used as a solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators, and osmotic pressure regulators in this field can be added.
  • the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents can also be added to the pharmaceutical preparations, if necessary.
  • the active ingredient or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs.
  • the active ingredient of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.
  • the invention relates to the application of penfluridol in the preparation of medicine for treating endometrial cancer.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the endometrial cancer includes progesterone-sensitive endometrial cancer or progesterone-resistant endometrial cancer.
  • the endometrial cancer is progesterone receptor-negative and progesterone-resistant endometrial cancer.
  • the drug for treating endometrial cancer is penfluridol.
  • the drug for treating endometrial cancer is a single component of penfluridol or a combination of penfluridol and other pharmaceutically acceptable components.
  • the mass percentage of the active component penfluridol is 0.1-99%.
  • the other pharmaceutically acceptable ingredients are anti-endometrial cancer drugs.
  • the anti-endometrial cancer drug is progesterone.
  • the progestin is one of megestrol acetate, medroxyprogesterone acid or progesterone caproate.
  • the dosage form of the drug is one of injection, tablet, capsule, pill, suspension or emulsion.
  • the drug formulation is administered orally or injected.
  • the invention provides the application of penfluridol in the preparation of medicine for treating endometrial cancer, and the endometrial cancer includes type I and type II endometrial cancer.
  • the present invention finds through experiments that penfluridol has an inhibitory effect on the proliferation, clone formation, and migration of endometrial cancer ISK and KLE cells, and can inhibit the growth of subcutaneous transplanted tumors in mice, which has been proved to be effective in mice in vivo experiments, thereby Penfluridol was found to have an unexpected effect in the treatment of endometrial cancer.
  • the main advantages of the present invention include:
  • penfluridol can inhibit the proliferation, colony formation and migration of endometrial cancer ISK and KLE cells.
  • penfluridol can inhibit the growth of subcutaneous endometrial cancer xenografts in mice.
  • Endometrial cancer cells ISK and KLE were purchased from the American Type Culture Collection (ATCC); phosphate buffered saline (PBS) was purchased from Bio-channel; DMEM/F12 medium was purchased from Biosharp; fetal calf Serum (FBS) and trypsin were purchased from Gibco; CCK-8 was purchased from Biyuntian Biotechnology Co., Ltd.; penfluridol was from the old drug library of the laboratory.
  • ATCC American Type Culture Collection
  • PBS phosphate buffered saline
  • DMEM/F12 medium was purchased from Biosharp
  • FBS fetal calf Serum
  • trypsin were purchased from Gibco
  • CCK-8 was purchased from Biyuntian Biotechnology Co., Ltd.
  • penfluridol was from the old drug library of the laboratory.
  • ISK and KLE cells were cultured in DMEM/F12 (containing 10% fetal bovine serum, 1% penicillin/streptomycin) medium and placed in an incubator at 37°C and 5% CO 2 .
  • the endometrial cancer cells basically covered the cell culture dish (10 cm)
  • the cells were digested with trypsin, and seeded in a 96-well plate at a cell density of 5000 cells/well, 100 ⁇ L per well.
  • DMEM/F12 medium containing different concentrations of PFL was added, 200 ⁇ L per well, and 3 replicate wells were set up for each group. Incubate in cell culture incubator for 24h, 48h or 72h respectively.
  • Inhibition rate calculation formula: cell inhibition rate% [1-(administration group A value-blank group A value)/(control group A value-blank group A value)] ⁇ 100%, IC50 value through Graphpad Prism 8.0 software fit.
  • Penfluridol inhibited the proliferation of ISK cells at incubation times of 24h, 48h, and 72h with IC 50 of 4.65 ⁇ M, 3.48 ⁇ M, and 2.77 ⁇ M; penfluridol inhibited the proliferation of KLE cells at incubation times of 24h, 48h, and 72h
  • the active IC 50 were 5.86 ⁇ M, 3.14 ⁇ M, 2.88 ⁇ M, respectively.
  • penfluridol can inhibit the proliferation of endometrial cancer cells ISK and KLE in a time-dependent and concentration-dependent manner.
  • penfluridol can inhibit the colony formation ability of endometrial cancer cells ISK and KLE, and can inhibit the colony formation of endometrial cancer cells in a concentration-dependent manner.
  • 0.5% crystal violet dye solution was purchased from Beyontian Biotechnology Co., Ltd. Methanol is a common reagent in the laboratory and was purchased commercially without any treatment. All the other experimental materials are from the same sources as in Example 1.
  • the EC cells in the logarithmic growth phase were digested with trypsin to prepare a single cell suspension, seeded into a 6-well plate at a density of about 1000 cells per well, and cultured overnight. After the cells adhered to the wall, they were divided into 4 groups, namely the control group, the PFL 2 ⁇ M group, the PFL 3 ⁇ M group and the PFL 4 ⁇ M group, with 3 replicate wells in each group.
  • the drug-administered group was cultured with 2 mL of DMEM/F12 medium containing different concentrations of drugs for 48 hours, and then replaced with a drug-free medium to continue culturing for about 8 days. After the cells grow into a cell group visible to the naked eye, place them on ice, and wash the cells twice with pre-cooled PBS for 3 minutes each time. Cells were then fixed with pre-cooled methanol for 10 min at -20°C. Suction methanol, add crystal violet staining solution 1mL, stain for 30min. Remove the crystal violet dye solution and wash with water until the dye solution is completely eluted. Invert the 6-well plate and wait for it to dry, take pictures with a gel imager, count manually with Image J software, and count the number of clones formed in each well.
  • the vertical axis of the histogram indicates the number of cell communities in each group, and the significant difference of data was analyzed by One-way ANOVA method (Graphpad Prism 8.0 software). Data are mean ⁇ SD: *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001 vs Ctrl.
  • penfluridol has an inhibitory effect on the colony formation of ISK and KLE cells, and can inhibit the colony formation of endometrial cancer cells ISK and KLE in a concentration-dependent manner.
  • penfluridol can inhibit the migration of endometrial cancer cells ISK and KLE, and can inhibit the migration of endometrial cancer cells in a concentration-dependent manner.
  • the Transwell chamber was purchased from Costar Company; paraformaldehyde is a common reagent in the laboratory, commercially purchased without any treatment, and the sources of other experimental materials are the same as in Example 1.
  • the EC cells in the logarithmic growth phase were digested with trypsin, prepared into a single cell suspension using serum-free DMEM/F12 medium, and seeded on the top of the Transwell chamber at a density of about 100,000 cells per well. Add 600 ⁇ L of DMEM/F12 medium containing 20% FBS to the bottom of the small chamber, taking care to avoid the generation of air bubbles.
  • penfluridol has the ability to inhibit the migration of ISK and KLE cells, and can inhibit the migration of endometrial cancer cells in a concentration-dependent manner.
  • the Annexin V-FITC/PI cell apoptosis detection kit was used to test the effect of penfluridol on the apoptosis of endometrial cancer cells ISK and KLE at the cellular level.
  • the research results show that penfluridol can inhibit the apoptosis of endometrial cancer cells ISK and KLE, and can inhibit the apoptosis of endometrial cancer cells in a concentration-dependent manner.
  • the Annexin V-FITC/PI Cell Apoptosis Detection Kit was purchased from Beyotime Biotechnology Co., Ltd., in which Annexin V-FITC Conjugate Solution, Annexin V-FITC, and Propidium Iodide (PI) are all reagents in the kit. All the other experimental materials are from the same sources as in Example 1.
  • the EC cells in the logarithmic growth phase were digested with trypsin to prepare a single cell suspension, seeded into a 6-well plate at a density of about 120,000 cells per well, and cultured overnight.
  • the cells adhered to the wall they were divided into 4 groups, namely the control group, the PFL 2 ⁇ M group, the PFL 3 ⁇ M group and the PFL 4 ⁇ M group, with 3 replicate wells in each group.
  • the treatment group was added with 2 mL of DMEM/F12 medium containing different concentrations of PFL, and the control group was added with 2 mL of drug-free DMEM/F12 medium. Incubate for 48 h at 37°C in an incubator with 5% CO 2 .
  • the percentages of apoptosis were 12.11%, 27.34% and 31.83% when the concentration of penfluridol was 2 ⁇ M, 3 ⁇ M and 4 ⁇ M, respectively.
  • the vertical axis of the histogram indicates the proportion of apoptosis in each group, and the significant difference of the data is analyzed by One-way ANOVA method (Graphpad Prism8.0 software). Data are mean ⁇ SD: *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001 vs Ctrl.
  • penfluridol has the ability to induce apoptosis of ISK and KLE cells, and can induce the apoptosis of ISK and KLE cells in a concentration-dependent manner.
  • mice of SPF grade 5-6 weeks old female BALB/C nude mice of SPF grade were selected as experimental animals, which were purchased from Shanghai Slack Animal Experiment Co., Ltd.; cisplatin (DDP) was obtained from the old drug storehouse of the laboratory.
  • the compound preparation method is to take a certain amount of compound, dissolve it in DMSO and castor oil (the final concentration of DMSO is 5%, and the final concentration of castor oil is 8%), then dilute it into the required concentration with normal saline, and the corresponding solvent is given to the control group. .
  • Compounds are formulated and used immediately prior to administration.
  • mice were implanted subcutaneously in the right armpit of 5-6 week-old nude mice, and about 5 million cells were implanted in each mouse. After the tumor grew to 800-1000 mm 3 , the mice were sacrificed, and then the tumor tissue was cut into tumor tissue pieces of uniform size, which were transplanted into new 5-6 week-old nude mice under the skin of the right armpit. When the newly grown tumor volume reached an average of 300-400 mm 3 , the mice were randomly divided into 4 groups: control group, positive drug DDP 2 mg/kg, PFL 2 mg/kg administration group, and PFL 5 mg/kg administration group. Inject 0.1 mL intraperitoneally according to different drug concentrations, and weigh the mice every day.

Abstract

La présente invention concerne le domaine technique des médicaments, et en particulier, une application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre. Les études de la présente invention montrent que la pentafluorine a pour effet d'inhiber la prolifération, la formation de clones et la capacité de migration des cellules ISK et KLE du cancer de l'endomètre, peut induire l'apoptose de cellules EC, peut inhiber la croissance de tumeurs greffées sous-cutanées de souris, se révèle efficace dans des expériences chez des souris, et a un potentiel d'application dans le traitement du cancer de l'endomètre.
PCT/CN2021/117534 2021-09-09 2021-09-09 Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre WO2023035200A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202180100160.1A CN117642164A (zh) 2021-09-09 2021-09-09 五氟利多在制备治疗子宫内膜癌的药物中的应用
PCT/CN2021/117534 WO2023035200A1 (fr) 2021-09-09 2021-09-09 Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/117534 WO2023035200A1 (fr) 2021-09-09 2021-09-09 Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre

Publications (1)

Publication Number Publication Date
WO2023035200A1 true WO2023035200A1 (fr) 2023-03-16

Family

ID=85507137

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/117534 WO2023035200A1 (fr) 2021-09-09 2021-09-09 Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre

Country Status (2)

Country Link
CN (1) CN117642164A (fr)
WO (1) WO2023035200A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016062285A1 (fr) * 2014-10-24 2016-04-28 朗齐生物医学股份有限公司 Utilisation d'un médicament pour le traitement des maladies immunitaires en vue de la préparation d'une composition pharmaceutique anticancéreuse

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016062285A1 (fr) * 2014-10-24 2016-04-28 朗齐生物医学股份有限公司 Utilisation d'un médicament pour le traitement des maladies immunitaires en vue de la préparation d'une composition pharmaceutique anticancéreuse

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HE SUQIAN, CHENG YU-XIA; QI HUANG-PENG; ZHOU PING; FANG LEI; SUN QING: "Analysis of Clinicopathological Features and Prognosis Factors in 198 Patients with Endometrial Cancer", CHINESE JOURNAL OF CANCER PREVENTION AND TREATMENT, vol. 26, no. 20, 31 October 2019 (2019-10-31), pages 1562 - 1568, XP093046401, DOI: 10.16073/j.cnki.cjcpt.2019.20.13 *
HENDOUEI NARJES, SAGHAFI FATEMEH, SHADFAR FAEZEH, HOSSEINIMEHR SEYED JALAL: "Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment", EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 856, 1 August 2019 (2019-08-01), NL , pages 172402, XP093046402, ISSN: 0014-2999, DOI: 10.1016/j.ejphar.2019.05.031 *
NGUYEN MINH TUAN ET AL.: "Penfluridol as a Candidate of Drug Repurposing for Anticancer Agent.", MOLECULES, vol. 24, 11 October 2019 (2019-10-11), XP055862789, DOI: 10.3390/molecules24203659 *
RANJAN ALOK, GUPTA PARUL, SRIVASTAVA SANJAY K.: "Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 76, no. 4, 15 February 2016 (2016-02-15), US, pages 877 - 890, XP093046400, ISSN: 0008-5472, DOI: 10.1158/0008-5472.CAN-15-1233 *
VIKRAM SHAW ET AL.: "Repurposing Antipsychotics of the Diphenylbutylpiperidine Class for Cancer Therapy.", SEMINARS IN CANCER BIOLOGY, vol. 68, 13 October 2019 (2019-10-13), XP086481949, DOI: 10.1016/j.semcancer.2019.10.007 *

Also Published As

Publication number Publication date
CN117642164A (zh) 2024-03-01

Similar Documents

Publication Publication Date Title
WO2002036592A1 (fr) Remedes aux maladies causees par l'acide arachidonique
WO2019174571A1 (fr) Composition pharmaceutique et son utilisation dans la préparation d'un médicament pour le traitement d'une résistance multi-médicament de tumeur
JP2004517915A (ja) 新生物疾患を治療するための薬物併用方法（例えば、クロルプロマジンおよびペンタミジン）
CN111759853B (zh) 一种药物组合物及其用途
CN111184863B (zh) 酪氨酸激酶抑制剂、cdk4/6抑制剂、serd联合在制备治疗肿瘤的药物中的用途
WO2019214723A1 (fr) Application de l'acide chlorogénique et de compositions de ce dernier dans la préparation de médicaments pour le traitement du carcinome épidermoïde
JP5211073B2 (ja) 子宮内膜症の治療用の薬剤
WO2023035200A1 (fr) Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre
CN112641775A (zh) 鸦胆子苦醇及其类似物在垂体腺瘤治疗中的应用
EA001325B1 (ru) Способы лечения и профилактики интерстициального цистита
CN115192573B (zh) 盐酸去亚甲基小檗碱在制备治疗肺纤维化药物中的应用
WO2020072774A1 (fr) Thérapie combinée pour le traitement du mélanome de la choroïde
JP2018513130A (ja) Ｈｓｐ９０阻害ペプチド結合体及びその腫瘍治療における応用
CN109876000A (zh) 帕布昔利布在黏膜恶性黑色素瘤中的应用
WO2023035201A1 (fr) Application de penfluridol combiné à de l'acétate de médroxyprogestérone dans la préparation d'un médicament pour le traitement du cancer de l'endomètre
WO2021023291A1 (fr) Utilisation de proflavine dans le traitement de cancers du poumon
CN113350325A (zh) 二蒽酮类化合物在制备抗肿瘤药物中的应用
KR20140032586A (ko) Ｐｔｅｎ 기능저하에 의한 ｅｇｆｒ-ｔｋｉ 저해제-내성 폐암의 방사선 치료용 약학 조성물
WO2017194030A1 (fr) Utilisation de l'inhibiteur du fonctionnement des protéines dapt dans la préparation d'un médicament pour le traitement de maladies endocriniennes
CN107569493A (zh) 氟维司群在制备治疗无功能垂体腺瘤的药物中的用途
TWI835118B (zh) 布瑞哌唑口溶膜組合物、其製備方法及用途
CN113769097A (zh) Egfr/her2抑制剂联合嘧啶类抗代谢药物的用途
CN114929682B (zh) 苯并硫代吡喃酮类化合物的盐及其制备方法和用途
CN113181187B (zh) 三氟拉嗪在制备治疗卒中后脑水肿药物组合物中的应用
WO2023078366A1 (fr) Composition de film orale soluble de chlorhydrate de lurasidone, procédé de préparation et utilisation associés

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21956384

Country of ref document: EP

Kind code of ref document: A1