CN109602760B - Composition of platinum compound and heparin compound and application thereof - Google Patents
Composition of platinum compound and heparin compound and application thereof Download PDFInfo
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- CN109602760B CN109602760B CN201811641364.2A CN201811641364A CN109602760B CN 109602760 B CN109602760 B CN 109602760B CN 201811641364 A CN201811641364 A CN 201811641364A CN 109602760 B CN109602760 B CN 109602760B
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to the field of organic synthesis and pharmaceutical chemistry, and particularly discloses a composition of a platinum compound and a heparin compound and application thereof. The composition of the platinum compound and the heparin compound disclosed by the invention can be applied to preparing antitumor drugs, has an obvious antitumor effect on cancer cells, and specifically comprises the following components: combining an antithrombotic drug, namely a heparin compound, with a platinum anti-tumor compound, so that the sensitivity of tumor cells to the platinum compound is enhanced; the anti-tumor effect of the platinum compound is obviously improved; the composition has obvious anti-tumor effect and can effectively relieve the side effect caused by single administration of the platinum compound.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to a composition of a platinum compound and a heparin compound and application thereof in preparing an anti-tumor medicament.
Background
Cancer is a common frequently-occurring disease seriously harming human health, and overcoming malignant tumors is a hot problem of domestic and foreign research. To date, methods for treating tumors include surgical resection, radiation therapy, chemotherapy, and the like. Among them, chemotherapy is predominant because it is safer and suitable for most patients. At present, platinum anti-tumor compounds become indispensable medicines in cancer chemotherapy and have the widest application range. Since 1978, cisplatin was first approved as a first-generation antitumor Drug by Food and Drug Administration (FDA), platinum antitumor drugs began to enter the visual field of people and were rapidly applied to clinical treatment of various malignant tumors, and platinum antitumor compounds such as carboplatin, nedaplatin, oxaliplatin, leplatin, heptaplatin, lobaplatin, and miboplatin were listed in various countries. Domestic and foreign researches show that after the platinum compounds enter cells of a human body, most of the conjugates generated by combining the platinum compounds with substances in the cells can have cytotoxicity, so that the platinum compounds have the effect of resisting tumors. The mechanism of action of platinum antineoplastic compounds with cancer cells can be summarized by the following steps: after being injected into cells, the platinum anti-tumor compound is hydrolyzed in cytoplasm and reacts with water to form a positively charged hydrate, and the positively charged hydrate enters cell nucleus under the action of electrostatic attraction to form a complex with DNA, so that the replication and transcription of the DNA are hindered, and the apoptosis of the cells is caused.
Heparin is a glycosaminoglycan, a mixture of polysaccharide chains with different chain lengths, consisting of uronic acid and glucosamine. The molecular weight of heparin is between 3000 and 30000Da, and the average molecular weight is about 15000 Da. Heparin is an anticoagulant and antithrombotic drug, and in the heparin chain, a unique pentasaccharide unit exists, can react with antithrombin and is transmitted through the antithrombin, and is one of the most important antithrombotic and anticoagulant drugs at present. The low molecular weight heparin is a general name of heparin with lower molecular weight prepared by depolymerizing common heparin, and the side effect of the low molecular weight heparin is lower than that of the heparin.
Disclosure of Invention
In order to solve the problems of large toxic and side effects and poor sensitivity of tumor cells to platinum drugs when the platinum drugs are independently administered in the prior art, the invention aims to provide a novel composition, which consists of a platinum anti-tumor compound and a heparin compound and application thereof in preparing anti-tumor drugs.
The invention is realized by the following technical method:
a composition of platinum compound and heparin compound comprises platinum compound and heparin compound.
Preferably, the molar ratio of the heparin compound to the platinum compound is 0.005-64; the platinum compound is one or more of cisplatin, lobaplatin and oxaliplatin; the heparin compound is one or more of low molecular weight heparin calcium, enoxaparin sodium, dalteparin sodium and heparin sodium.
Preferably, the composition consists of low molecular weight heparin calcium and lobaplatin in a molar ratio of 0.12-20;
or the composition consists of enoxaparin sodium and lobaplatin according to the molar ratio of 0.14-22.2;
or the composition consists of dalteparin sodium and lobaplatin according to the molar ratio of 0.17-22.2;
or the composition consists of heparin sodium and lobaplatin according to the molar ratio of 0.02-3.4;
or the composition consists of low molecular weight heparin calcium and cisplatin in a molar ratio of 0.02-29.70;
or the composition consists of enoxaparin sodium and cisplatin in a molar ratio of 0.03-33.33;
or the composition consists of dalteparin sodium and cisplatin in a molar ratio of 0.03-42;
or the composition consists of heparin sodium and cisplatin in a molar ratio of 0.005-5;
or the composition consists of low molecular weight heparin calcium and oxaliplatin according to the molar ratio of 0.5-64;
or the composition consists of enoxaparin sodium and oxaliplatin according to the molar ratio of 0.5-64;
or the composition consists of dalteparin sodium and oxaliplatin according to the molar ratio of 0.5-64;
or the composition consists of heparin sodium and oxaliplatin according to the molar ratio of 0.5-13.3.
Preferably, the composition of the platinum compound and the heparin compound is applied to preparing antitumor drugs.
Preferably, the anti-tumor is one or more of anti-liver cancer, anti-pancreatic cancer, anti-lung cancer, anti-colorectal cancer, anti-breast cancer and anti-cervical cancer.
Preferably, the composition of the platinum compound and the heparin compound is applied to preparing an anti-tumor medicament which is combined with a conventional anti-tumor medicament.
The invention has the beneficial effects that:
(1) the evaluation of the Q value of the inhibition effect of the combination of the two compounds on cancer cell lines shows that the composition of the invention has good tumor inhibition effect on cancer cell lines.
(2) According to the invention, the platinum compound and the heparin compound are combined and applied to the preparation of the antitumor drug, so that the antitumor effect is obviously improved, and the combined antitumor effect is better.
(3) According to the composition of the platinum compound and the heparin compound, the effect of the heparin compound can reduce the dosage of the platinum medicine, correspondingly improve the sensitivity of tumor cells to the platinum compound and the drug resistance of tumor tissues to the platinum medicine, and can effectively relieve the side effect caused by single administration of the platinum compound; the two compounds in the composition have different types and different inhibition effects on cancer cell strains, and the synergistic effect of the two compounds obviously improves the anti-tumor effect of the composition.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but the scope of the present invention is not limited to the specific examples, but is defined by the claims.
Example 1
Cell lines and culture: 2 strains of liver cancer cells (BEL-7402, Hep-G2), 5 strains of pancreatic cancer cells (BxPC-3, Capan-1, Colo357, Miapaca-2, Panc-1), 6 strains of lung cancer cells (A427, A549, NCI-H1299, NCI-H2170, NCI-H358, NCI-H460), 3 strains of colorectal cancer cells (Colo205, Lovo, RKO), 6 strains of breast cancer cells (HCC-1806, MCF-7, MDA-MB-231, MDA-MB-361, MDA-436, TD-47), 1 strain of cervical cancer cells (Hela), these cells were donated by Nanjing university, DMEM/RPMI 1640/McCoy' 5a medium containing 10% fetal bovine serum at 37 ℃, (DMEM-c),5％CO2Culturing in an incubator, changing the culture solution once in 2-3 days, and taking the cells in the logarithmic growth phase for experiment.
Cell proliferation assay (MTT method): preparing 2 × 10 cancer cells in logarithmic growth phase4Each cell/mL suspension was added at 100. mu.L per well in a 96-well plate. A reagent control group, a tumor cell control group and experimental groups of various medicines with different concentrations are arranged. Before the experiment, the single medicines of cisplatin, lobaplatin and oxaliplatin are respectively added into tumor cells, so that the final concentrations of the cisplatin, lobaplatin and oxaliplatin are 5ng/mL, 50ng/mL, 500ng/mL, 5000ng/mL and 50000ng/mL, and therefore the IC50 concentrations of the three medicines are known, heparin compounds with different concentrations are added, and then the following combined experiment is started. Experimental component single drug groups and combined drug groups. The reagent control group was supplemented with an equal amount of medium, and the tumor cell control group was supplemented with an equal amount of the same medium without drug, 3 parallel wells per dose. In CO2After 24h of culture in an incubator, 10 mu L of 0.5 percent MTT is added into each well for further culture for 4h, 100 mu L of triple dissolving solution is added, the mixture is decolorized overnight until the MTT is completely dissolved, and the absorbance (A) of each well is measured at 570nm and 630nm of an automatic enzyme-labeled reading instrument, and the inhibition rate and IC50 are measured.
And (4) analyzing results:
(1) combined administration of lobaplatin and low molecular weight heparin calcium:
lobaplatin was administered in combination with low molecular heparin calcium, and the results are shown in table 1. According to analysis, for the hepatoma carcinoma cell Bel7402, when the molar ratio of the low-molecular heparin calcium to the lobaplatin in the composition is 1-4, the inhibition rate of the composition on tumors is increased by 138% -164%; for liver cancer cells HepG2, when the molar ratio of low molecular weight heparin calcium to lobaplatin in the composition is 4, the inhibition rate of the composition on tumors is increased by 122%; for pancreatic cancer cells BxPC-3, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.12-4, the inhibition rate of the composition on tumors is increased by 117% -181%; for pancreatic cancer cells Colo357, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.25-4, the inhibition rate of the composition on tumors is increased by 111% -156%; for pancreatic cancer cells Capan-1, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.25-4, the inhibition rate of the composition on tumors is increased by 112% -129%; for pancreatic cancer cells Panc-1, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 2-4, the inhibition rate of the composition on tumors is increased by 108% -113%; for pancreatic cancer cells Miapaca-2, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 3.3-5.7, the inhibition rate of the composition on tumors is increased by 116% -124%; for pancreatic cancer cells, Capan-2, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.2-5.7, the inhibition rate of the composition on tumors is increased by 109% -133%; for the lung cancer cell A427, when the molar ratio of the low-molecular heparin calcium to the lobaplatin in the composition is 2-4, the inhibition rate of the composition on tumors is increased by 238 percent; for lung cancer cells NCI-H1299, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.12-4, the inhibition rate of the composition on tumors is increased by 108% -115%; for lung cancer cells NCI-H2170, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 2-4, the inhibition rate of the low-molecular heparin calcium to lobaplatin on tumors is increased by 268% -270%; for lung cancer cells NCI-H358, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.12-4, the inhibition rate of the composition on tumors is increased by 118% -204%; for lung cancer cells NCI-H460, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 2-4, the inhibition rate of the composition on tumors is increased by 120%; for lung cancer cells A549, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 5-20, the inhibition rate of the composition on tumors is increased by 148% -161%; for colorectal cancer cells Colo205, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.12-4, the inhibition rate of the composition on tumors is increased by 105% -130%; for colorectal cancer cells LoVo, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 4, the inhibition rate of the composition on tumors is increased by 128%; for colorectal cancer cells RKO, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 20, the inhibition rate of the low-molecular heparin calcium to lobaplatin on tumors is increased by 184 percent; for breast cancer cells HCC1806, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 4, the inhibition rate of the composition on tumors is increased by 145 percent; for breast cancer cells MCF-7, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 2-4, the inhibition rate of the composition on tumors is increased by 149-156%; for breast cancer cells TD-47, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 1-4, the inhibition rate of the composition on tumors is increased by 133-219%; for breast cancer cells MM-436, when the molar ratio of low molecular heparin calcium to lobaplatin in the composition is 13.3, the inhibition rate of the composition on tumors is increased by 161%; for breast cancer cells MM231, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 5.7-13.3, the inhibition rate of the composition on tumors is increased by 164-240%; for the cervical cancer cell Hela, when the molar ratio of the low molecular weight heparin calcium to the lobaplatin in the composition is 13.3, the inhibition rate of the low molecular weight heparin calcium to the lobaplatin on the tumor is increased by 109 percent. The inhibition rate data of the combined administration of lobaplatin and low molecular weight heparin calcium on each tumor cell are shown in table 1:
TABLE 1
(2) Co-administration of lobaplatin and enoxaparin sodium:
lobaplatin was administered in combination with enoxaparin sodium, and the results are shown in table 2. According to analysis, for hepatoma carcinoma cell Bel7402, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 0.56, the inhibition rate of enoxaparin sodium to lobaplatin on tumors is increased by 118%; for pancreatic cancer cells Colo357, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 0.28-4.4, the inhibition rate of enoxaparin sodium to tumor is increased by 117% -130%; for pancreatic cancer cells Panc-1, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 2.2-4.4, the inhibition rate of the composition on tumors is increased by 119% -123%; for pancreatic cancer cells, Capan-2, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 7.3, the inhibition rate of the enoxaparin sodium to lobaplatin on tumors is increased by 135%; for the lung cancer cell A427, when the molar ratio of the enoxaparin sodium to the lobaplatin in the composition is 0.56-4.3, the inhibition rate of the enoxaparin sodium to the tumor is increased by 123-135 percent; for the lung cancer cell NCI-H1299, when the molar ratio of the enoxaparin sodium to the lobaplatin in the composition is 0.56, the inhibition rate of the enoxaparin sodium to the lobaplatin on tumors is increased by 121 percent; for the lung cancer cell NCI-H2170, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 0.14, the inhibition rate of the enoxaparin sodium to lobaplatin on tumors is increased by 122%; for lung cancer cells NCI-H358, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 0.14-0.56, the inhibition rate of enoxaparin sodium to lobaplatin is increased by 119% -124%; for the lung cancer cell NCI-H460, when the molar ratio of the enoxaparin sodium to the lobaplatin in the composition is 4.4, the inhibition rate of the enoxaparin sodium to the lobaplatin on tumors is increased by 112 percent; for lung cancer cell A549, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 22, the inhibition rate of enoxaparin sodium to lobaplatin on tumors is increased by 136%; for the breast cancer cell MM231, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 14.7, the inhibition rate of the enoxaparin sodium to lobaplatin on tumors is increased by 138%; for the cervical cancer cell Hela, when the molar ratio of enoxaparin sodium to lobaplatin in the composition is 3.6, the inhibition rate of enoxaparin sodium to lobaplatin on tumors is increased by 117%. The inhibition rate of the combined administration of lobaplatin and enoxaparin sodium on each tumor cell is shown in table 2:
TABLE 2
(3) Lobaplatin in combination with dalteparin sodium:
lobaplatin was administered in combination with dalteparin sodium, with the results shown in table 3. According to analysis, for pancreatic cancer cells Colo357, when the molar ratio of dalteparin sodium to lobaplatin in the composition is 0.35-5.57, the inhibition rate of the composition on tumors is increased by 118% -133%; for pancreatic cancer cells Panc-1, when the molar ratio of dalteparin sodium to lobaplatin in the composition is 1.39-5.57, the inhibition rate of the composition on tumors is increased by 121% -133%; for pancreatic cancer cells Capan-2, when the molar ratio of dalteparin sodium to lobaplatin in the composition is 0.29-9.3, the inhibition rate of the composition on tumors is increased by 107% -139%; for the lung cancer cell A427, when the molar ratio of the dalteparin sodium to the lobaplatin in the composition is 0.35-5.57, the inhibition rate of the dalteparin sodium to the lobaplatin on tumors is increased by 122-154%; for lung cancer cell NCI-H2170, when the molar ratio of the daparinux sodium to the lobaplatin in the composition is 2.78, the inhibition rate of the composition on tumors is increased by 136%; for lung cancer cells NCI-H358, when the molar ratio of dalteparin sodium to lobaplatin in the composition is 0.17-5.57, the inhibition rate of the composition on tumors is increased by 134% -150%; for lung cancer cells A549, when the molar ratio of the dalteparin sodium to the lobaplatin in the composition is 2.8-22.2, the inhibition rate of the dalteparin sodium to the lobaplatin is increased by 122% -136%; for colorectal cancer cells Lovo, when the molar ratio of dalteparin sodium to lobaplatin in the composition is 0.7-2.78, the inhibition rate of the composition on tumors is increased by 122% -128%; for breast cancer cells HCC1806, when the molar ratio of the dalteparin sodium to the lobaplatin in the composition is 0.7 and 2.78, the inhibition rate of the composition on tumors is increased by 115 percent; for breast cancer cells MM-436, when the molar ratio of dalteparin sodium to lobaplatin in the composition is 18.6, the inhibition rate of the composition on tumors is increased by 150%. The inhibition rate of lobaplatin and dalteparin sodium on each tumor cell is shown in table 3:
TABLE 3
(4) Combined administration of lobaplatin and heparin sodium:
lobaplatin was administered in combination with heparin sodium, and the results are shown in table 4. According to analysis, for pancreatic cancer cells Colo357, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.33-0.67, the inhibition rate of the composition on tumors is increased by 122% -124%; for pancreatic cancer cells, namely, the Capan-1, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.02-0.67, the inhibition rate of the composition on tumors is increased by 112% -140%; for pancreatic cancer cells Panc-1, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.17-0.67, the inhibition rate of the composition on tumors is increased by 132% -135%; for pancreatic cancer cells, Capan-2, when the molar ratio of heparin sodium to lobaplatin in the composition is 1.1, the inhibition rate of heparin sodium to lobaplatin on tumors is increased by 126%; for the lung cancer cell A427, when the molar ratio of the heparin sodium to the lobaplatin in the composition is 0.02-0.67, the inhibition rate of the composition on tumors is increased by 143-180%; for the lung cancer cell NCI-H1299, when the molar ratio of the heparin sodium to the lobaplatin in the composition is 0.12 and 0.67, the inhibition rate of the composition on tumors is increased by 111 percent; for lung cancer cells NCI-H358, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.02-0.67, the inhibition rate of the composition on tumors is increased by 126% -143%; for lung cancer cells A549, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.1-3.4, the inhibition rate of the composition on tumors is increased by 119-129%; for breast cancer cells HCC1806, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.02-0.67, the inhibition rate of the composition on tumors is increased by 116-126%; for breast cancer cells TD-47, when the molar ratio of heparin sodium to lobaplatin in the composition is 0.33-0.67, the inhibition rate of the composition on tumors is increased by 132-159%; for the cervical cancer cell Hela, when the molar ratio of the heparin sodium to the lobaplatin in the composition is 2.2, the inhibition rate of the composition on the tumor is increased by 113%. The inhibition rate of lobaplatin and heparin sodium on each tumor cell is shown in table 4:
TABLE 4
(5) Cisplatin and low molecular heparin calcium combined administration:
cisplatin was co-administered with low molecular heparin calcium and the results are shown in table 5. According to analysis, for the hepatoma carcinoma cell Bel7402, when the molar ratio of the low-molecular heparin calcium to the cisplatin in the composition is 1.49-2.97, the inhibition rate of the low-molecular heparin calcium to the cisplatin on tumors is increased by 134 percent; for pancreatic cancer cells BxPC-3, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 7.42-14.83, the inhibition rate of the composition on tumors is increased by 120% -126%; for pancreatic cancer cells Colo357, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 7.42-14.83, the inhibition rate of the composition on tumors is increased by 135-138%; for pancreatic cancer cells Miapaca-2, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 1.49-2.97, the inhibition rate of the composition on tumors is increased by 131% -134%; for pancreatic cancer cells, namely, the Capan-2, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 3.71-14.83, the inhibition rate of the composition on tumors is increased by 120-143%; for the lung cancer cell A427, when the molar ratio of the low-molecular heparin calcium to the cisplatin in the composition is 1.85-7.41, the inhibition rate of the low-molecular heparin calcium to the cisplatin on tumors is increased by 191-229%; for the lung cancer cell NCI-H1299, when the molar ratio of the low molecular weight heparin calcium to the cisplatin in the composition is 2.47 and 9.88, the inhibition rate of the low molecular weight heparin calcium to the cisplatin on tumors is increased by 124 percent; for the lung cancer cell NCI-H2170, when the molar ratio of the low molecular weight heparin calcium to the cisplatin in the composition is 4.94-9.88, the inhibition rate of the low molecular weight heparin calcium to the cisplatin on tumors is increased by 116%; for lung cancer cells NCI-H460, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 3.71-7.41, the inhibition rate of the low-molecular heparin calcium to cisplatin to tumors is increased by 175-176%; for lung cancer cells A549, when the molar ratio of the low-molecular heparin calcium to the cisplatin in the composition is 3.71-29.65, the inhibition rate of the low-molecular heparin calcium to the cisplatin on tumors is increased by 400-967 percent; for colorectal cancer cells Colo205, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 0.93-14.83, the inhibition rate of the composition on tumors is increased by 132% -153%; for colorectal cancer cells Lovo, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 14.85-29.7, the inhibition rate of the composition on tumors is increased by 226-240%; for breast cancer cells HCC1806, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 7.4, the inhibition rate of the composition on tumors is increased by 135%; for breast cancer cells TD-47, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 1.49-2.97, the inhibition rate of the composition on tumors is increased by 132-138 percent; for breast cancer cells MM-436, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 7.42-14.83, the inhibition rate of the composition on tumors is increased by 151-159 percent; for breast cancer cells MM231, when the molar ratio of low-molecular heparin calcium to cisplatin in the composition is 14.85-29.7, the inhibition rate of the composition on tumors is increased by 244% -322%; for the cervical cancer cell Hela, when the molar ratio of the low molecular weight heparin calcium to the cisplatin in the composition is 29.7, the inhibition rate of the low molecular weight heparin calcium to the cisplatin on the tumor is increased by 126 percent. The low molecular weight heparin calcium has very weak cytotoxic effect on most tumor cells, which indicates that the low molecular weight heparin calcium has little or very weak anti-tumor effect. The inhibition rate of cisplatin and low-molecular heparin calcium on each tumor cell is shown in table 5:
TABLE 5
(6) Cisplatin and enoxaparin sodium co-administration:
cisplatin was co-administered with enoxaparin sodium and the results are shown in table 6. Analysis shows that for the cervical cancer cell Hela, when the molar ratio of the enoxaparin sodium to the cisplatin in the composition is 0.26-1.04, the inhibition rate of the enoxaparin sodium to the cisplatin on tumors is increased by 121-131%. Enoxaparin sodium did not show any cytotoxic effect on all tumor cells within the determined concentration range.
TABLE 6
(7) Cisplatin and dalteparin sodium co-administration:
cisplatin was co-administered with dalteparin sodium and the results are given in table 7. For pancreatic cancer cells Miapaca-2, when the molar ratio of the dalteparin sodium to the cisplatin in the composition is 1.05-4.2, the inhibition rate of the composition on tumors is increased by 109% -114%; for lung cancer cell A549, when the molar ratio of the dalteparin sodium to the cisplatin in the composition is 42, the inhibition rate of the composition on tumors is increased by 218%; for colorectal cancer cells Colo205, when the molar ratio of the dalteparin sodium to the cisplatin in the composition is 0.22-0.88, the inhibition rate of the composition on tumors is increased by 112% -121%; for colorectal cancer cells HF-29, when the molar ratio of dalteparin sodium to cisplatin in the composition is 0.26-2.1, the inhibition rate of the composition on tumors is increased by 152-274%; for the cervical cancer cell Hela, when the molar ratio of the dalteparin sodium to the cisplatin in the composition is 0.33, the inhibition rate of the composition on the tumor is increased by 114%. Within the determined concentration range, dalteparin sodium did not show any cytotoxic effect on all tumor cells.
TABLE 7
(8) Cisplatin and heparin sodium co-administration:
cisplatin was co-administered with heparin sodium and the results are shown in table 8. According to analysis, for the hepatoma carcinoma cell Bel7402, when the molar ratio of heparin sodium to cisplatin in the composition is 0.25-0.5, the inhibition rate of the composition on tumors is increased by 110-114%; for the liver cancer cell HepG2, when the molar ratio of the heparin sodium to the cisplatin in the composition is 2.5, the inhibition rate of the composition on tumors is increased by 125 percent; for pancreatic cancer cells Colo357, when the molar ratio of heparin sodium to cisplatin in the composition is 2.5, the inhibition rate of the composition on tumors is increased by 111%; for pancreatic cancer cells Panc-1, when the molar ratio of heparin sodium to cisplatin in the composition is 0.5, the inhibition rate of the composition on tumors is increased by 113%; for pancreatic cancer cells Miapaca-2, when the molar ratio of heparin sodium to cisplatin in the composition is 0.25-0.5, the inhibition rate of the composition on tumors is increased by 109%; for the lung cancer cell A427, when the molar ratio of the heparin sodium to the cisplatin in the composition is 125-2.5, the inhibition rate of the composition on tumors is increased by 125-157%; for the lung cancer cell NCI-H1299, when the molar ratio of the heparin sodium to the cisplatin in the composition is 0.21 and 0.84, the inhibition rate of the heparin sodium to the cisplatin on tumors is increased by 131 percent; for the lung cancer cell NCI-H460, when the molar ratio of the heparin sodium to the cisplatin in the composition is 0.63-1.25, the inhibition rate of the heparin sodium to the cisplatin on tumors is increased by 125-130%; for colorectal cancer cells Colo205, when the molar ratio of heparin sodium to cisplatin in the composition is 0.01-0.05, the inhibition rate of the composition on tumors is increased by 132%; for breast cancer cells MM231, when the molar ratio of heparin sodium to cisplatin in the composition is 5, the inhibition rate of the composition on tumors is increased by 129%; for the cervical cancer cell Hela, when the molar ratio of the heparin sodium to the cisplatin in the composition is 0.625-5, the inhibition rate of the composition on tumors is increased by 114% -122%. Heparin sodium showed no cytotoxic effect on almost all tumor cells within the concentration range determined.
TABLE 8
(9) Oxaliplatin in combination with low molecular weight heparin calcium:
oxaliplatin was administered in combination with low molecular weight heparin calcium, and the results are shown in table 9. According to analysis, for the hepatoma carcinoma cell Bel7402, when the molar ratio of the low-molecular heparin calcium to the oxaliplatin in the composition is 16-64, the inhibition rate of the composition on tumors is increased by 223%; for pancreatic cancer cells BxPC-3, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 154-163%; for pancreatic cancer cells Miapaca-2, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 16-64, the inhibition rate of the composition on tumors is increased by 307-319 percent; for pancreatic cancer cells Capan-2, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 0.5-64, the inhibition rate of the composition on tumors is increased by 142% -308%; for the lung cancer cell A427, when the molar ratio of the low-molecular heparin calcium to the oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 180-263%; for lung cancer cells NCI-H2170, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 1.35-21.55, the inhibition rate of the low-molecular heparin calcium to tumors is increased by 224% -314%; for lung cancer cells NCI-H358, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the low-molecular heparin calcium to the tumors is increased by 200-251%; for lung cancer cells NCI-H460, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 4-64, the inhibition rate of the low-molecular heparin calcium to the tumors is increased by 161-224%; for lung cancer cells A549, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 4-64, the inhibition rate of the composition on tumors is increased by 212-266%; for colorectal cancer cells Colo205, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 5.39-43.10, the inhibition rate of the composition on tumors is increased by 137-154 percent; for colorectal cancer cells Lovo, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 190% -321%; for colorectal cancer cells RKO, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 1-64, the inhibition rate of the composition on tumors is increased by 117-140 percent; for breast cancer cells MCF-7, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 158-231%; for breast cancer cells TD-47, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 220-242%; for breast cancer cells MM-436, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 166% -173%; for breast cancer cells MM231, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 163-181%; for a cervical cancer cell Hela, when the molar ratio of low-molecular heparin calcium to oxaliplatin in the composition is 16-64, the inhibition rate of the composition on tumors is increased by 297-303%. In most of the concentration ranges determined, low molecular heparin calcium showed no cytotoxic effect on almost all tumor cells.
TABLE 9
(10) Inhibition rate of combined administration of oxaliplatin and enoxaparin sodium:
oxaliplatin and enoxaparin sodium were co-administered and the results are given in table 10. According to analysis, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 0.5-64, the inhibition rate of the pancreatic cancer cells BxPC-3 on tumors is increased by 111-127%; for pancreatic cancer cells, Capan-2, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 0.5-32, the inhibition rate of the composition on tumors is increased by 189% -267%; for lung cancer cells NCI-H358, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 16-64, the inhibition rate of the composition on tumors is increased by 111-144%; for lung cancer cells NCI-H460, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 8-64, the inhibition rate of the composition on tumors is increased by 115-144%; for colorectal cancer cells Colo205, when the molar ratio of low-molecular heparin calcium to lobaplatin in the composition is 0.5, the inhibition rate of the composition on tumors is increased by 123 percent; for colorectal cancer cells Lovo, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 0.5-8, the inhibition rate of the composition on tumors is increased by 146-157 percent; for breast cancer cells MM-436, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 0.5-64, the inhibition rate of the composition on tumors is increased by 113% -166%; for the breast cancer cell MM231, when the molar ratio of enoxaparin sodium to oxaliplatin in the composition is 64, the inhibition rate of the composition on tumors is increased by 115%. Enoxaparin sodium showed almost no cytotoxic effect on all tumor cells over the range of concentrations determined.
Watch 10
(11) Oxaliplatin in combination with dalteparin sodium:
oxaliplatin and dalteparin sodium were co-administered, and the results are given in table 11. According to analysis, for hepatoma carcinoma cell Bel7402, when the molar ratio of the dalteparin sodium to the oxaliplatin in the composition is 644, the inhibition rate of the composition on tumors is increased by 163 percent; for pancreatic cancer cells BxPC-3, when the molar ratio of the daparinux sodium to the oxaliplatin in the composition is 0.5-64, the inhibition rate of the composition on tumors is increased by 110-120%; for pancreatic cancer cells Miapaca-2, when the molar ratio of the daparinux sodium to the oxaliplatin in the composition is 64, the inhibition rate of the composition on tumors is increased by 177%; for pancreatic cancer cells Capan-2, when the molar ratio of the dalteparin sodium to the oxaliplatin in the composition is 0.5-32, the inhibition rate of the composition on tumors is increased by 186-229%; for the lung cancer cell A427, when the molar ratio of the dalteparin sodium to the oxaliplatin in the composition is 64, the inhibition rate of the composition on tumors is increased by 174%; for lung cancer cells NCI-H460, when the molar ratio of the dalteparin sodium to the oxaliplatin in the composition is 16-64, the inhibition rate of the composition on tumors is increased by 138% -173%. Within the vast majority of the concentration ranges measured, dalteparin sodium showed no cytotoxic effect on all tumor cells.
TABLE 11
(12) Oxaliplatin in combination with heparin sodium:
oxaliplatin and heparin sodium were administered in combination, and the results are shown in table 12. According to analysis, for hepatoma carcinoma cell Bel7402, when the molar ratio of heparin sodium to oxaliplatin in the composition is 64, the inhibition rate of the composition on tumors is increased by 142%; for pancreatic cancer cells Miapaca-2, when the molar ratio of heparin sodium to oxaliplatin in the composition is 64, the inhibition rate of the composition on tumors is increased by 205 percent; for the lung cancer cell NCI-H2170, when the molar ratio of the heparin sodium to the oxaliplatin in the composition is 2.22, the inhibition rate of the composition on tumors is increased by 141%; for colorectal cancer cells RKO, when the molar ratio of heparin sodium to oxaliplatin in the composition is 1.66-6.65, the inhibition rate of the composition on tumors is increased by 133-138%; for breast cancer cells TD-47, when the molar ratio of heparin sodium to oxaliplatin in the composition is 6.65-13.3, the inhibition rate of the composition on tumors is increased by 121-142%. Heparin sodium showed almost no cytotoxic effect on all tumor cells over the vast majority of the concentration range measured.
TABLE 12
In addition to the investigation of the inhibition rate of the combination of the platinum compound and the heparin compound, the invention also studies the inhibition rate of the single administration of the platinum compound on the tumor and the inhibition rate of the single administration of the heparin compound on the tumor. Since the inhibition rate is significantly less than that of the combination when administered alone, the inhibition rate of the individual administration is not overly described in the methods of the invention.
(13) The inhibition rate of platinum compounds administered alone is shown in table 13:
watch 13
(14) The inhibition rate of enoxaparin sodium administration alone is shown in table 14:
TABLE 14
(15) The inhibition rate of daparinux sodium administered alone is shown in table 15:
watch 15
(16) The inhibition rate of heparin sodium administration alone was as shown in table 16:
TABLE 16
The invention combines the platinum compound and the heparin compound and applies the platinum compound and the heparin compound to the preparation of the antitumor drugs. The two medicines are combined for use, so that the dosage of the platinum medicine can be reduced, and the combined anti-tumor effect is better; the combination of the two can improve the sensitivity of tumor cells to platinum drugs; the platinum compounds have different types, and the anti-tumor effect of the composition is different; the heparin compounds have different types, and the anti-tumor effect of the composition is different; the combination of the platinum compound and the heparin compound has a certain dosage relation.
The invention also tries that the types and specific varieties of other cell strains except liver cancer cell strains, pancreatic cancer cell strains, lung cancer cell strains, colorectal cancer cell strains, breast cancer cell strains and cervical cancer cell strains mentioned in the specification generate certain tumor inhibition effect; the invention also tries to combine platinum compounds except lobaplatin, cisplatin and oxaliplatin with heparin compounds, thereby generating certain effect of enhancing and inhibiting tumors; the invention also tries to combine the molecular heparin calcium, enoxaparin sodium, dalteparin sodium and heparin compounds except heparin sodium with different platinum compounds for administration, thus enhancing the anti-tumor effect; the present invention also attempts to further improve the antitumor effect by combining a combination of a platinum-based compound and a heparin-based compound with a conventional antitumor compound.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention, and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A composition of a platinum compound and a heparin compound, wherein the composition comprises the platinum compound and the heparin compound;
the platinum compound is one or more of cisplatin, lobaplatin and oxaliplatin; the heparin compound is one or more of low molecular weight heparin calcium, enoxaparin sodium, dalteparin sodium and heparin sodium;
the composition consists of low molecular weight heparin calcium and lobaplatin in a molar ratio of 0.12-20;
or the composition consists of enoxaparin sodium and lobaplatin according to the molar ratio of 0.14-22.2;
or the composition consists of dalteparin sodium and lobaplatin according to the molar ratio of 0.17-22.2;
or the composition consists of heparin sodium and lobaplatin according to the molar ratio of 0.02-3.4;
or the composition consists of low molecular weight heparin calcium and cisplatin in a molar ratio of 0.02-29.70;
or the composition consists of enoxaparin sodium and cisplatin in a molar ratio of 0.03-33.33;
or the composition consists of dalteparin sodium and cisplatin in a molar ratio of 0.03-42;
or the composition consists of heparin sodium and cisplatin in a molar ratio of 0.005-5;
or the composition consists of low molecular weight heparin calcium and oxaliplatin according to the molar ratio of 0.5-64;
or the composition consists of enoxaparin sodium and oxaliplatin according to the molar ratio of 0.5-64;
or the composition consists of dalteparin sodium and oxaliplatin according to the molar ratio of 0.5-64;
or the composition consists of heparin sodium and oxaliplatin according to the molar ratio of 0.5-13.3.
2. The use of a platinum compound and a heparin compound composition according to claim 1 in the preparation of an anti-tumor medicament.
3. The use of the composition of a platinum compound and a heparin compound according to claim 2 in the preparation of an anti-tumor medicament, wherein the anti-tumor medicament is one or more of anti-liver cancer, anti-pancreatic cancer, anti-lung cancer, anti-colorectal cancer, anti-breast cancer and anti-cervical cancer.
4. The use of the composition of a platinum compound and a heparin compound in the preparation of an anti-tumor medicament according to claim 2, wherein the use is in the preparation of an anti-tumor medicament used in combination with a conventional anti-tumor medicament.
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