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WO2013037127A1 - Composition pharmaceutique antitumorale et utilisation de celle-ci - Google Patents

Composition pharmaceutique antitumorale et utilisation de celle-ci Download PDF

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WO2013037127A1
WO2013037127A1 PCT/CN2011/079757 CN2011079757W WO2013037127A1 WO 2013037127 A1 WO2013037127 A1 WO 2013037127A1 CN 2011079757 W CN2011079757 W CN 2011079757W WO 2013037127 A1 WO2013037127 A1 WO 2013037127A1
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tumor
dexamethasone
dipyridamole
pharmaceutical composition
weight ratio
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PCT/CN2011/079757
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Chinese (zh)
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刘秀均
甄永苏
郑艳波
李毅
吴淑英
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中国医学科学院医药生物技术研究所
浙江普洛康裕制药有限公司
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Priority to PCT/CN2011/079757 priority Critical patent/WO2013037127A1/fr
Publication of WO2013037127A1 publication Critical patent/WO2013037127A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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 present invention is in the field of medicinal chemistry, and in particular, relates to an antitumor drug composition and use thereof. Background technique
  • the strategy for developing new anti-tumor drugs includes two aspects: finding drugs for tumor cells and drugs for regulating tumor microenvironment.
  • drugs acting on tumor cells mainly induce tumor cell proliferation, induce tumor cell apoptosis, and induce tumor cells. Differentiation works.
  • the drugs that regulate the tumor microenvironment mainly play the role of inhibiting tumor angiogenesis or interfering with tumor vascular network; regulating immune cells and related cytokines in tumor infiltration; regulating growth factor secretion and growth factor receptor expression; Inhibition of specific enzyme secretion and regulation of corresponding inhibitors; Interfering with the transport, uptake and efflux of intracellular and extracellular substances in tumor cells.
  • Dipyr idamole is a non-tumor therapeutic drug synthesized in the 1980s. Its pharmaceutically acceptable derivatives or analogues such as mopidamole, BIBW22BS, RA25 or its pharmacy
  • An acceptable salt is a non-nitrate coronary artery dilator that has the effect of expanding the coronary vessels and promoting the formation of collateral circulation. Dipyridamole also has the effect of inhibiting platelet aggregation and preventing thrombosis.
  • the drug is included as a cardiovascular dilating agent in the Pharmacopoeia of the People's Republic of China (2000 edition) and the United States Pharmacopoeia (XXI-XXI II), but because of its so-called "coronary theft” phenomenon, ie heparin, coumarins and fibrin When dissolved drugs are combined, they can cause bleeding tendency, so they have become clinically unnecessary.
  • Dipyridamole is a potent nucleoside transport inhibitor in the mechanism of drug action by blocking the balanced nucleoside transporter hENTl (Nat Med, 1997, 3: 89-93) and hENT2 (Biochem. J, 1997, 328: 739-43) inhibits nucleoside transport.
  • Ubenimex (Bes tat in, BEN) and pharmaceutically acceptable derivatives or analogs thereof include AHPA-VaK Bestat in Hydrochloride and the like.
  • Ubumex is a small molecule dipeptide compound isolated from the fermentation broth of Streptomyces ol ivoret icul i by Japanese scholar Umezawa in 1976. It can competitively inhibit various aminopeptidase activities. It exerts a dual anti-tumor effect by promoting the immune function of the body and directly acting on tumor tissues. In 1987, it was marketed as a new anticancer drug with immunomodulatory function in Japan for the adjuvant treatment of malignant tumors.
  • Ubumex exhibits a multi-faceted immune activity that not only enhances lymphocyte function, but also activates monocyte macrophages to enhance the killing activity of NK cells.
  • Molecular mechanism studies have shown that its target is leucine aminopeptidase (Leu-AP) and aminopeptidase B (AP-B) located on the surface of immune cells, which can catalyze the cleavage of the amino terminus of the substrate to make the antigen The molecule is inactivated.
  • Ubumex inhibits the activity of aminopeptidase by chelation with zinc ions in the active center of the enzyme. Due to its immune-enhancing function, Ubumex is often used in the treatment of tumor chemotherapy, radiotherapy and postoperative surgery. It can be combined with chemotherapy, radiotherapy and combined therapy for leukemia, multiple myeloma and solid tumors such as lung cancer and breast cancer.
  • Ubumex can also exert anti-tumor activity by directly acting on tumor tissues.
  • Aminopeptidase N (CD13) is highly expressed in tumor neovascular endothelial cells, which promotes tumor vascular formation by degrading extracellular matrix, promoting endothelial cell invasion, and regulating the activity of certain growth factors and cytokines (Int J Cancer, 1993) , 54: 137-43).
  • Certain tumor cells such as human fibrosarcoma HT-1080 cell aminopeptidase N, also exhibit high expression and are closely related to invasion and metastasis of tumor cells (Int J Cancer, 1993, 54: 137-43).
  • Ubumex can inhibit the activity of aminopeptidase N, thereby effectively inhibiting the formation of tumor blood vessels and preventing the metastasis of tumor cells.
  • Ubumex can also directly induce tumor cell apoptosis (Biomed Pharmacother. 1996; 50: 283-9), thereby exerting an anti-tumor effect.
  • Glucocorticoids such as dexamethasone (Dexamethason, DEX) and pharmaceutically acceptable derivatives or analogs thereof, such as dexamethasone acetate, dexamethasone sodium silicate, dexamethasone palmitate, hydrocortisone , cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone and other pharmacological effects such as anti-inflammatory, immunosuppressive, anti-toxin, anti-shock.
  • DEX dexamethasone
  • pharmaceutically acceptable derivatives or analogs thereof such as dexamethasone acetate, dexamethasone sodium silicate, dexamethasone palmitate, hydrocortisone , cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone and other pharmacological effects such as anti-inflammatory, immunosuppressive,
  • glucocorticoids include the C3 carbonyl group, the ⁇ 4 and 17 ⁇ ketol side chains of the adrenocortical hormone, and the 17 ⁇ - 0 ⁇ and 11 ⁇ - ⁇ unique to glucocorticoids.
  • glucocorticoids not only include endogenous substances with the above characteristics and activities, but also many synthetic drugs with similar structure and activity optimized by structure.
  • glucocorticoid drugs are a kind of clinical application. drug.
  • GR Glucocort icoid Receptor
  • glucocorticoid-receptor complex is located at the apex of the inflammatory regulatory network and is capable of inhibiting multiple inflammatory pathways.
  • glucocorticoids induce and activate Annexin I, induce MKP-1 and inhibit C0X-2 transcription, inhibit prostaglandin synthesis, and control inflammatory responses.
  • glucocorticoid-receptor complexes can also rapidly regulate inflammation through non-transcriptional pathways (Nat Med, 2002 8: 473-9). Tumors are closely related to inflammation, and the occurrence of inflammation promotes the development of tumors. Dexamethasone controls the inflammatory response through multiple pathways and inhibits tumor development.
  • Dexamethasone also inhibits tumor angiogenesis, and Yano A uses prostate cancer. Studies conducted have shown that dexamethasone inhibits tumor blood vessels (Cl in Cancer Res, 2006, 12: 3003-9) and lymphangiogenesis (Cl in Cancer Res, 2006, 12: 6012-7), Wilson C et al. Studies have shown that dexamethasone enhances the anti-tumor angiogenesis activity of docetaxel (Br J Cancer, 2008, 99: 2054-64).
  • dexamethasone can reduce some side effects of chemotherapy in cancer patients, and reduce the symptoms of nausea and vomiting after chemotherapy.
  • Dexamethasone is also commonly used in the treatment of some hematological malignancies.
  • thal/dex thal/dex
  • thal/dex thal/dex
  • dexamethasone with cyclophosphamide, vincristine and doxorubicin Hyper-CVAD
  • Hyper-CVAD doxorubicin
  • dexamethasone is commonly used to inhibit the permeability of tumor-associated blood vessels to reduce the development of edema.
  • dipyridamole and dexamethasone are used as non-antitumor drugs for cardiovascular and anti-inflammatory drugs.
  • Dexamethasone is only used as an adjunct to hematologic malignancies, and Ubmen is only The adjuvant anti-tumor drugs are not used as first-line anti-tumor drugs. Summary of the invention
  • the present inventors hope to find a novel pharmaceutical composition which is low in toxicity, high in efficiency, and capable of comprehensively regulating the tumor microenvironment. After intensive research and creative labor, a novel pharmaceutical composition is obtained, and it is surprisingly found that the pharmaceutical composition The substance has a good anti-tumor effect (significantly superior to the effect of any one of the components alone), and the toxic side effect is small.
  • the following invention is thus provided:
  • One aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising two or three of the following three components (active ingredients) of A, B and C:
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant.
  • the pharmaceutical composition is an antitumor pharmaceutical composition. More specifically, the tumor is selected from one or more of liver cancer, squamous cell carcinoma, lung cancer, and pancreatic cancer.
  • composition according to any one of the present invention, wherein the pharmaceutically acceptable derivative of dipyridamole is one or more selected from the group consisting of mopidamole, BIBW BS and RA25.
  • the pharmaceutically acceptable derivative of dipyridamole also includes a pharmaceutically acceptable salt of dipyridamole.
  • the pharmaceutical composition according to any one of the present invention wherein the pharmaceutically acceptable derivative of umbrel is AHPA-Val and/or Bes tat in Hydrochloride.
  • the pharmaceutically acceptable derivative of ursinide also includes a pharmaceutically acceptable salt of umbrel.
  • the pharmaceutical composition according to any one of the present invention wherein the pharmaceutically acceptable derivative of dexamethasone is selected from the group consisting of dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone sodium sulphate, and hydrogenated One or more of pine, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, and betamethasone.
  • the pharmaceutically acceptable derivative of dexamethasone also includes a pharmaceutically acceptable salt of dexamethasone.
  • a pharmaceutical composition according to any one of the present invention which is characterized by any one or more of the following (1) to (13):
  • the pharmaceutical composition of the present invention can be produced by a conventional method in the pharmaceutical field.
  • a conventional physical mixing method may be carried out by mixing two or three of the A, B or C.
  • the invention adopts the clone formation method to detect the in vitro cytotoxicity of the drug, and uses the mouse tumor model and the human cancer tumor mouse transplantation model to observe the in vivo experimental effect of the drug.
  • cytology and molecular biology methods were used to study the mechanism of action of effective drugs, and histotoxicity was studied by histopathological methods. Animal Tests It has been confirmed that the antitumor drug of the present invention has remarkable antitumor activity in animals and has low systemic toxicity, and is expected to be a new drug having antitumor activity.
  • Another aspect of the invention relates to the use of a pharmaceutical composition according to any of the inventions in the manufacture of an antitumor drug or a medicament or agent for inhibiting tumor cells in vivo or in vitro.
  • the tumor is selected from one or more of liver cancer, squamous cell carcinoma, lung cancer, and pancreatic cancer.
  • a further aspect of the invention relates to a method of anti-tumor comprising the step of administering to a subject an effective amount of a pharmaceutical composition according to any one of the inventions.
  • the tumor is selected from the group consisting of liver cancer, squamous cell carcinoma, lung cancer, and pancreatic cancer. One or more.
  • the anti-tumor pharmaceutical composition of the present invention can be orally administered to a patient in need of treatment in the form of a composition, and the dosage is generally from 100 to 500 mg/person/day, depending on the age, weight and condition of the patient. Etc., determined by the physician.
  • a further aspect of the invention relates to a method of inhibiting tumor cells in vivo or in vitro, comprising the step of using an effective amount of a pharmaceutical composition according to any of the inventions.
  • the tumor is selected from one or more of liver cancer, squamous cell carcinoma, lung cancer, and pancreatic cancer.
  • pharmaceutically acceptable carrier or adjuvant means a conventional pharmaceutical carrier or adjuvant in the pharmaceutical field, such as a diluent, an excipient such as water, a filler, such as starch, sucrose, etc., a binder such as a cellulose derivative. Gelatin, polyvinylpyrrolidone, etc., lubricants, such as talc.
  • an effective amount refers to a dose that can achieve treatment, prevention, alleviation, and/or alleviation of a disease or condition described herein in a subject.
  • subject can refer to a patient or other animal that receives the composition of the invention to treat, prevent, ameliorate and/or alleviate the disease or condition of the invention, particularly a mammal, such as a human, a dog, a monkey, a cow, Horse and so on.
  • the present invention provides a novel antitumor pharmaceutical composition which is effective for the treatment of tumors mainly by acting on the tumor microenvironment.
  • the pharmaceutical composition of the present invention is characterized by the regulation of tumor microenvironment drugs which act on multiple targets and multiple pathways; the side effects caused by cytotoxic drugs are expected to be alleviated.
  • the invention combines dipyridamole, umbrel and dexamethasone for the treatment of tumors.
  • Dipyridamole, umbrel and dexamethasone are not cytotoxic drugs, so when used alone, there is only moderate antitumor effect at tolerable doses. About 20-60%.
  • the inventors combined the three and two, and found that the tumor inhibition rate can be increased to 60-70%.
  • the present inventors have surprisingly discovered that the combination of dipyridamole, umbrel and dexamethasone has significant anti-tumor activity in animals, and the tumor inhibition rate can reach more than 90%, for human liver cancer, human lung cancer.
  • the treatment effect of human pancreatic cancer is much better than the corresponding clinical first-line drugs 5-fluorouracil, gemcitabine, capecitabine, etc., for human epidermal cancer A431 with high expression of epidermal growth factor receptor (EGFR), its therapeutic effect and clinical
  • the first-line drug gefitinib is equally effective, and the system toxicity is extremely low, and it is expected to be a pharmaceutical composition with high anti-tumor activity.
  • the combination of dipyridamole, umbrel and dexamethasone 22, and the combination of the three for tumor treatment are the first, and no relevant reports have been reported at home and abroad.
  • Fig 1 dipyridamole, ubenimex combination of dexamethasone inhibition of tumor growth in mice liver cancer H 22.
  • Fig. 2 Tumor growth inhibition effect of dipyridamole, umbrel and dexamethasone on transplanted human liver cancer BEL-7402.
  • Fig. 3 Inhibition of tumor growth by transplanting human hepatoma HepG2 into mice by dipyridamole, umbrel and dexamethasone.
  • Fig. 4 Inhibition of tumor growth by transplanting human squamous cell carcinoma A431 with dipyridamole, umbrel and dexamethasone.
  • Fig. 5 Inhibition of tumor growth by transplanting human lung cancer PG with dipyridamole, umbrel and dexamethasone.
  • Fig. 6 Tumor growth inhibition effect of dipyridamole, umbrel and dexamethasone on transplanted human lung cancer A549.
  • Fig. 7 Inhibition of tumor growth by transplanting human pancreatic MPAC with dipyridamole, umbrel and dexamethasone.
  • Fig. 8 Inhibition of tumor growth by transplanting human pancreas SW1990 with dipyridamole, umbrel and dexamethasone.
  • Fig. 9 Pathological section of pathological examination of various organ tissues of HepG2 mice bearing dipyridamole, umbrel and dexamethasone.
  • the tissue and sample administration used in Fig. 9A - Fig. 9P are as follows:
  • Fig. 10 Wes tern blot to detect the effect of drugs on the expression of tissue protein in transplanted tumor of mouse liver cancer H 22 mice.
  • Fig. 11 Effect of two-dimensional electrophoresis on the expression of tissue protein in human liver cancer Be-Bad 7402 mice.
  • Fig. 11A is the control group
  • Fig. 11 B is the DPM+BEN+DEX group. detailed description
  • the abbreviations of the respective drugs are: dipyridamole (DPM), umbrel (BEN), and dexamethasone (DEX).
  • Example 1 Preparation of a sample of a composition comprising dipyridamole and umbrelzine: Dipyridamole, 'J is 1 mg, 10 mg, 100 mg, 200 mg, 300 mg, 400 mg, 900 mg or 1600 mg, Uzbek Division 1
  • Another J is 1mg, 10mg, 20mg, 40mg, 60mg, 80mg, 100mg, 300mg, 900mg, 1600mg or 3200mg, dipyridamole and umbrel can be mixed and mixed. As shown in Table 1, the intersection in the table is the recipe.
  • Table 1 Formulations of compositions containing dipyridamole and umbrel
  • Example 2 Preparation of a sample of a composition comprising dipyridamole and dexamethasone: Dipyridamole, 'J is 1 mg, 10 mg, 100 mg, 200 mg, 300 mg, 400 mg, 900 mg or 1600 mg, dexamethasone Further, 'J is 0.1 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg or 160 mg. Mix dipyridamole and dexamethasone, and mix. As shown in Table 2, the intersection in the table is For the recipe.
  • Table 2 Formulations of compositions containing dipyridamole and dexamethasone
  • Example 3 Preparation of a sample of a composition comprising umbrel and dexamethasone:
  • Ubimetrex is 1 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 300 mg, 900 mg, 1600 mg or 3200 mg, respectively.
  • Dexamethasone is divided into '1 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg or 160 mg.
  • Formulation 1 The formulation of Example 1 is mixed with 0.1 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg or 160 mg of dexamethasone, respectively.
  • Formulation 2 The formulation of Example 2 was mixed with 1 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 300 mg, 900 mg, 1600 mg or 3200 mg of urinium, respectively.
  • Example 3 The formulation of Example 3 was mixed with 1 mg, 10 mg, 100 mg, 200 mg, 300 mg, 400 mg, 900 mg or 1600 mg of dipyridamole, respectively.
  • Example 5 In vitro cytotoxicity test of drugs
  • Drugs and Reagents Dipyridamole: Standard, purchased from China National Institute for the Control of Pharmaceutical and Biological Products; Ubumex: API, Zhejiang Plo Kangyu Pharmaceutical Co., Ltd.; Dexamethasone: Standard, purchased from China Pharmaceutical and Biological Products Laboratory; 5-fluorouracil injection for Shanghai Xudong Haipu Pharmaceutical Co., Ltd.;
  • liver cancer BEL-7402 cells were purchased from the Cell Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences.
  • Test drug A sample of the pharmaceutical composition selected from the preparation of Examples 1 - 4.
  • Example 6 In vivo antitumor activity of drugs The inhibition of tumor growth in a pair of mice
  • the test drug is selected from the samples of the pharmaceutical compositions prepared in Examples 1-4. Dipyridamole: Standard, purchased from China National Institute for the Control of Pharmaceutical and Biological Products; Ubumex: API, Zhejiang Plo Kangyu Pharmaceutical Co., Ltd.; Dexamethasone: Standard, purchased from China National Institute for the Control of Pharmaceutical and Biological Products; Pyramidazole tablets: Shanxi Yabao Pharmaceutical Group Co., Ltd. production; dexamethasone acetate tablets: Tianjin Lisheng Pharmaceutical Co., Ltd. production; Ubimex (Bai Shixin) plastic bottles: Zhejiang Plo Kangyu Pharmaceutical Co., Ltd.
  • Kunming mice (clean grade II) are female, 6-8 weeks old, weighing 18-22 g, provided by the Experimental Animal Center of the Academy of Military Medical Sciences, license number SCXK (Army) 2007-004.
  • Table 7 Inhibition of tumor growth of mouse liver cancer H 22 by dipyridamole combined with different doses of dexamethasone
  • Table 8 Inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of mouse liver cancer H 22
  • Table 9 Growth inhibition of mouse liver cancer H 22 by different doses of dipyridamole combined with umbrel and dexamethasone
  • Table 10 Inhibition of growth of mouse liver cancer H 22 by different doses of umbrel with dipyridamole and dexamethasone Dosage number of animals, body weight, tumor weight (g)
  • Table 11 Growth inhibitory effects of different doses of dexamethasone combined with dipyridamole and umbrel on liver cancer H 22 in mice
  • Fig. 1 The inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of mouse liver cancer H 22 .
  • Table 13 Effect of dipyridamole, umbrel and dexamethasone on mean survival time of mice bearing liver cancer H 22 Dose median survival time
  • Example 7 In vivo antitumor activity of drugs The growth inhibition of human tumors transplanted in a pair of mice
  • the test drug is selected from the sample of the pharmaceutical composition prepared in Example 4.
  • Dipyridamole Standard, purchased from China National Institute for the Control of Pharmaceutical and Biological Products;
  • Ubumex API, Zhejiang Plo Kangyu Pharmaceutical Co., Ltd.;
  • Dexamethasone Standard, purchased from China National Institute for the Control of Pharmaceutical and Biological Products;
  • Pyramidazole tablets Shanxi Yabao Pharmaceutical Group Co., Ltd. production; dexamethasone acetate tablets: Tianjin Lisheng Pharmaceutical Co., Ltd.
  • mice NIHnu/nu mice were female, 6-8 weeks old, weighing 18-22 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., license number SCXK (Beijing) 2006-0009.
  • mice Human tumor cells cultured in vitro were inoculated into the armpits of one side of NIHnu/nu mice. After 2-3 passages, the tumors were subcultured under the armpits and cut into small pieces of 1.5 legs and 3 pieces. The mice were subcutaneously on one side of the armpits. After the tumors were grown to 100 to 300 legs 3, they were randomly grouped according to tumor size, and oral administration was started. The control group was given physiological saline, and the other groups were administered with the drugs in the respective examples.
  • the inoculation was administered for 7 days, once a day for 10 times and sacrificed for 17 days. Compared with the control group *P ⁇ 0.01.
  • Table 15 Growth inhibition of dipyridamole, umbrel and dexamethasone on transplanted human liver cancer BEL-7402 (17d)
  • Fig. 2 Dipyridamole, Ubumex and Dexamethasone for transplantation of human liver Tumor growth inhibition of cancer BEL-7402.
  • Table 16 Growth inhibition of dipyridamole, umbrel and dexamethasone on human hepatoma HepG2 transplanted (28d)
  • the cells were administered for 7 days, and were administered 5 times a week for 3 weeks and 28 days, and no animals died in each group. Compared with the control group *P ⁇ 0.01.
  • Fig. 3 The inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of transplanted human hepatic carcinoma HepG2.
  • Fig. 4 The inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of transplanted human squamous cell carcinoma A431.
  • Table 18 Inhibition of tumor growth by transplanting human lung cancer PG with dipyridamole, umbrel and dexamethasone (17d)
  • Fig. 5 The inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of transplanted human lung cancer PG.
  • Table 19 Growth inhibition of lung cancer A549 in mice transplanted with dipyridamole, umbrel and dexamethasone (17 d )
  • the drug was administered for 7 days, once a day for 10 times, and gemcitabine was administered 3 times on days 7, 10, and 13, respectively. He died in 17 days. Compared with the control group * ⁇ 0. 01.
  • Table 20 Inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of transplanted human lung cancer A549 (28 d)
  • Fig. 6 The inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of transplanted human lung cancer A549.
  • the drug was administered for 7 days, once a day for 10 times, and the capecitabine was administered in the same manner as DPM+BEN+DEX, and was sacrificed at 17 days. Compared with the control group *P ⁇ 0. 01
  • Table 22 Tumor growth inhibition effect of dipyridamole, umbrel and dexamethasone on transplanted human pancreatic adenocarcinoma MPAC (28d)
  • DPM+BEN+DEX was administered 5 times a week for 3 weeks; capecitabine was administered in the same manner as DPM+BEN+DEX. Compared with the control group *P ⁇ 0.01.
  • Fig. 7 The inhibitory effect of dipyridamole, umbrel and dexamethasone on tumor growth of transplanted human pancreatic MPAC.
  • Table 23 Tumor growth inhibition effect of dipyridamole, umbrel and dexamethasone on transplanted human pancreatic cancer SW1990 (35d) Dosage Animals Body Weight Change Tumor Weight (g) Group Tumor Suppression Rate % (mg/kg) Start/End (g) SSD
  • the drug is administered 7 days after the tumor is inoculated, and DPM+BEN+DEX is administered 5 times a week. A total of 3 weeks; capecitabine administration is the same as DPM+BEN+DEX. Compared with the control group *P ⁇ 0.01.
  • the main organs were taken for pathological examination, and the bone marrow nucleated cells of the rats were counted.
  • the results are shown in Table 24, Fi g. 9. The results showed that there were no obvious pathological changes in the main organs such as heart, lung, liver, spleen, stomach, small intestine, kidney and femur (bone marrow).
  • the number of bone marrow nucleated cells was comparable to that of normal mice without tumor inoculation. Significant differences. It can be seen that the combination of dipyridamole, umbrel and dexamethasone did not lead to toxicity changes of cytotoxic drugs, indicating that the composition has good safety.
  • Table 24 Effect of dipyridamole, umbrel and dexamethasone on nucleated cells of bone marrow of human hepatoma HepG2 mice (pathological examination, average number of cells per field of view)
  • the tumor tissue was added 1:9 to the lysate (50 mM Tris ⁇ CI (pH 8.0), 150 mM NaCl, 0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate, 100 ⁇ g / ml PMSF, lug/ml Aprotinin, 0.02% sodium azide), low temperature homogenate, 4.
  • C is cleaved for 1 h, 10000 rpm 4 .
  • FLK1 and N0S3 decreased, and other detected proteins: EGF, The changes of VEGF, TGF, Beb2, k-Ras, P27, P21 and NF-kB were not obvious.
  • FLK1 is closely related to angiogenesis.
  • N0S is closely related to inflammation and plays an important role in the development of tumors (Clinical Chemother Pharmacol. 2011, 67 (6): 1211-24). This study shows dipyridamole.
  • the pharmaceutical composition of molybdenum, umbrel and dexamethasone may affect tumor angiogenesis and be associated with inflammatory responses.
  • Fig. 10 Wes tern blot was used to detect the effect of drugs on the expression of tissue protein in transplanted tumor of mouse liver cancer H 22 mice.
  • Tumor tissue proteomics study Two-dimensional electrophoresis: Two-dimensional electrophoresis was used to detect the effect of dipyridamole, umbrel and dexamethasone on the expression of human hepatocarcinoma in the transplanted tumor tissue of human liver cancer.
  • the sample was ground with liquid nitrogen through a pre-cooled metal sampler.
  • the TCA acetone method extracts whole proteins from tumor tissues and removes salts and impurities.
  • the extracted whole protein was quantified by Bradford, and each sample was taken with an equal amount of protein, and subjected to IEF isoelectric focusing (glue: PH3 - 10), and each was equilibrated with an equilibrium solution of 1% DTT and 2.5% IAM. 15 min, the strip was removed and transferred to a two-way gel, and the gel was run on a vertical plate polyacrylamide gel with a gel of 24 cm (adhesion of 12.5%).
  • Glue, fixed for 30min, sensitized for 30min washed with water 3 (each lOmin), silver stained, washed twice (each time lmin), color development, termination.
  • Glue scanning, glue analysis, three parallel glues for each sample were combined into a virtual glue, and the two sample virtual shares were compared and analyzed by GE's Imagemaster 2D version 5. 0.
  • Fig. 11 Two-dimensional electrophoresis detection of drug on the expression of human hepatoma Bel-7402 mouse transplanted tumor tissue protein. The figure shows a total of 17 change points: 4 more than 3 times change; 13 with or without, 12 of which are down, 1 on The results of the analysis are shown in Table 25, Table 26
  • the dexamethasone composition has a wide range of effects on protein metabolism, nucleoside metabolism, etc., and exerts anti-tumor effects through various effects.
  • Table 25 Proteins with more than three times the change and with or without.
  • Example 10 Acute toxicity test in mice with anti-tumor composition composed of dipyridamole, umbrel and dexamethasone
  • mice 60 Kunming mice were divided into 3 dose groups, 20 in each group, half male and half female. The difference ratio of each group was 0.8, the oral administration, the dose was 2. O g / kg, 1. 6 g / kg, 1. 28g / kg, observed for 14 days after the stomach administration and recorded the toxicity Including general indicators, death, weight changes, determination of toxicity, death, and calculation of median lethal dose in mice, pathological examination at the end of the experiment.
  • mice The symptoms of poisoning in the mice were normal, and the general indicators were normal. There were no deaths, weight loss and other symptoms. The body weight increased to 28 ⁇ 38 grams before the death on the 14th day after administration, and the appearance was healthy. Pathological examination was performed at the end of the experiment, and no obvious pathological changes were observed in the liver, kidney, lung and other major organs of the animals. The results showed that the anti-tumor new composition was very low in toxicity, especially for oral administration, and there was no significant difference between male and female animals. The oral LD50 (half lethal dose) of mice is greater than 2 g/kg. Through the acute toxicity test, it was proved that at a very high dose (mouse 2.

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Abstract

La présente invention appartient au domaine de la chimie médicale, et concerne une composition pharmaceutique antitumorale et son utilisation. En particulier, la composition pharmaceutique de la présente invention comporte deux ou trois ingrédients des trois composants suivants A, B et C : A. dipyridamole et/ou des dérivés pharmaceutiquement acceptables de celui-ci ; B ubénimex et/ou des dérivés pharmaceutiquement acceptables de celui-ci ; C dexaméthasone et/ou des dérivés pharmaceutiquement acceptables de celle-ci ; éventuellement, la composition pharmaceutique comprend également un support ou un excipient pharmaceutiquement acceptable. L'invention concerne également une utilisation de la composition pharmaceutique dans la préparation de médicaments antitumoraux et une méthode antitumorale. La composition pharmaceutique antitumorale de la présente invention remplit l'objectif de traitement des tumeurs de manière efficace principalement en agissant sur le micro-environnement tumoral, et les caractéristiques du médicament qui ajustent le microenvironnement tumoral font qu'il agit sur des cibles multiples et des voies multiples, ce qui peut être prévu pour atténuer les effets toxiques et secondaires provoqués par des médicaments cytotoxiques.
PCT/CN2011/079757 2011-09-16 2011-09-16 Composition pharmaceutique antitumorale et utilisation de celle-ci WO2013037127A1 (fr)

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TW200812589A (en) * 2006-05-22 2008-03-16 Combinatorx Inc Methods and compositions for the treatment of diseases or conditions associated with increased C-reactive protein, interleukin-6, or interferon-gamma levels
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10293019B2 (en) * 2014-12-17 2019-05-21 Delta-Fly Pharma, Inc. Pharmaceutical composition for treatment of or remission in elderly or terminal cancer patient

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