CN109602760A - A kind of composition and its application of platinum-like compounds and heparin-like compounds - Google Patents
A kind of composition and its application of platinum-like compounds and heparin-like compounds Download PDFInfo
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- CN109602760A CN109602760A CN201811641364.2A CN201811641364A CN109602760A CN 109602760 A CN109602760 A CN 109602760A CN 201811641364 A CN201811641364 A CN 201811641364A CN 109602760 A CN109602760 A CN 109602760A
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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 present invention relates to organic syntheses and field of medicinal chemistry, specifically disclose composition and its application of a kind of platinum-like compounds and heparin-like compounds.The composition of platinum-like compounds and heparin-like compounds disclosed by the invention, it can be applied in the preparation of antitumor drugs, it has apparent antitumous effect to cancer cell, it specifically includes: by antithrombotic reagent-heparin-like compounds, it is combined with platinum antineoplastic compound, so that tumour cell enhances the sensibility of platinum-like compounds；The antitumous effect of platinum-like compounds is obviously improved；Composition has apparent antitumor action, and brought side effect when platinum-like compounds are administered alone can be effectively relieved.
Description
Technical field
The present invention relates to organic syntheses and field of medicinal chemistry, and in particular to a kind of platinum-like compounds and heparin-like compounds
Composition and its application in preparation of anti-tumor drugs.
Background technique
Cancer is a kind of common frdquently encountered disease for seriously endangering human health, captures what malignant tumour was always studied both at home and abroad
Hot issue.So far, the method for treating tumour includes the methods of operation excision, radiotherapy, chemotherapy.Wherein, Chemo-Therapy
It treats in the highest flight, because its is safer and applicable for most of sufferer.Currently, platinum antineoplastic compound has become cancer
The most wide drug of indispensable and application range in disease chemotherapy.From cis-platinum in 1978 as first generation anti-tumor drug, through beauty
After state Food and Drug Administration (FDA) ratifies listing for the first time, platinum series antineoplastic medicament initially enters people
The visual field and by promptly be applied to various malignant tumours clinical treatment in, successively have carboplatin, Nedaplatin, oxaliplatin,
The platinum antineoplastics such as Lobaplatin, Eptaplatin, lobaplatin, Miboplatin compound is listed in various countries.Studies at home and abroad show that when platinum-like compounds into
After the cell for entering human body, the most conjugate generated in conjunction with intracellular matter can have cytotoxicity, to rise
To antineoplastic action.The mechanism of action of platinum antineoplastic compound and cancer cell can be summarized by following steps: platinum class is anti-
Neoplastic compound hydrolyzes in cytoplasm after injecting and entering cell, reacts to form positively charged hydrate with water,
Enter nucleus under electrostatic attraction effect, forms complex with DNA, the duplication and transcription of DNA are hindered, so as to cause cell
Apoptosis.
Heparin is a kind of glycosaminoglycan, is a kind of mixture with the polysaccharide chain of different chain length, it be by uronic acid and
Gucosamine composition.The molecular weight of heparin is between 3000-30000Da, average molecular weight about 15000Da or so.Heparin is
A kind of anticoagulation, antithrombotic drug, in heparin chain, there are a kind of unique pentasaccharides units, can be mutually with antithrombase
Phase reaction is simultaneously transmitted by it, is one of currently the most important ones antithrombotic, anticoagulation medicine.Low molecular weight heparin is by general
The general name for the lower heparin of molecule amount that logical heparin depolymerization is prepared, side effect are low compared with heparin.
Summary of the invention
Toxic side effect is big when for solution, platinum medicine is administered alone in the prior art and tumour cell is to the quick of platinum medicine
The problem of perceptual difference, the object of the present invention is to provide a kind of new composition, the composition by platinum antineoplastic compound and
Heparin-like compounds are formed and its application in preparation of anti-tumor drugs.
The present invention is realized by following technical method:
A kind of composition of platinum-like compounds and heparin-like compounds, is made of platinum-like compounds and heparin-like compounds
's.
Preferably, the molar ratio of the heparin-like compounds and the platinum-like compounds is 0.005~64；The platinum class
Conjunction object is one of cis-platinum, lobaplatin and oxaliplatin or a variety of；The heparin-like compounds are Low-molecular-weight Heparins Calcium, according to promise liver
One of plain sodium, Dalteparin Sodium and heparin sodium are a variety of.
Preferably, it is 0.12~20 to form that the composition, which is Low-molecular-weight Heparins Calcium and lobaplatin with molar ratio,；
Or it is 0.14~22.2 to form that the composition, which is Enoxaparin Sodium and lobaplatin with molar ratio,；
Or it is 0.17~22.2 to form that the composition, which is Dalteparin Sodium and lobaplatin with molar ratio,；
Or it is 0.02~3.4 to form that the composition, which is heparin sodium and lobaplatin with molar ratio,；
Or it is 0.02~29.7 to form that the composition, which is Low-molecular-weight Heparins Calcium and cis-platinum with molar ratio,；
Or it is 0.03~33.33 to form that the composition, which is Enoxaparin Sodium and cis-platinum with molar ratio,；
Or it is 0.03~42 to form that the composition, which is Dalteparin Sodium and cis-platinum with molar ratio,；
Or it is 0.005~5 to form that the composition, which is heparin sodium and cis-platinum with molar ratio,；
Or it is 0.5~64 to form that the composition, which is molecular heparin calcium and oxaliplatin with molar ratio,；
Or it is 0.5~64 to form that the composition, which is Enoxaparin Sodium and oxaliplatin with molar ratio,；
Or it is 0.5~64 to form that the composition, which is Dalteparin Sodium and oxaliplatin with molar ratio,；
Or it is 0.5~64 to form that the composition, which is heparin sodium and oxaliplatin with molar ratio,.
Preferably, the composition of a kind of platinum-like compounds and heparin-like compounds answering in the preparation of antitumor drugs
With.
Preferably, described antitumor for anti-liver cancer and anti-, anti-pancreatic cancer, anti-lung cancer, anti-colorectal carcinoma, anti-breast cancer and anti-uterine neck
One of cancer is a variety of.
Preferably, the composition of the platinum-like compounds and heparin-like compounds is combined in preparation with conventional anticancer drugs
Application in the anti-tumor drug of utilization.
The invention has the benefit that
(1) two kinds of compound combinations evaluate display, present invention combination to the Q value of the inhibiting effect of cancer cell line in the present invention
Object shows good tumor killing effect to cancer cell line.
(2) platinum-like compounds and heparin-like compounds are combined by the present invention, and are applied to and are prepared in anti-tumor drug,
Antitumous effect is obviously improved, and the antitumous effect after combination is more preferable.
(3) present invention in platinum-like compounds and heparin-like compounds composition, the effect of heparin-like compounds therein
The dosage that platinum medicine can be reduced correspondinglys increase tumour cell to the sensibility and tumor tissues of platinum-like compounds to platinum
The drug resistance of class drug, and brought side effect when platinum-like compounds are administered alone can be effectively relieved；Two in composition
The type of kind compound is different, also different to the inhibiting effect of cancer cell line, and the synergistic effect of the two is so that resisting for the composition
Tumor effect is obviously improved.
Specific embodiment
The present invention is described in further detail by the following examples, but protection scope of the present invention is not by specific reality
Any restrictions of example are applied, but are defined in the claims.
Embodiment 1
Cell line and culture: 2 plants of liver cancer cells (BEL-7402, Hep-G2), pancreatic cancer cell 5 plants of (BxPC-3, Capan-
1, Colo357, Miapaca-2, Panc-1), lung carcinoma cell 6 plants of (A427, A549, NCI-H1299, NCI-H2170, NCI-
H358, NCI-H460), 3 plants of colorectal cancer cell (Colo205, Lovo, RKO), breast cancer cell 6 plants of (HCC-1806, MCF-
7, MDA-MB-231, MDA-MB-361, MDA-MB-436, TD-47), 1 plant of cervical cancer cell (Hela), these cells are by Nanjing
University give, with contain 10% fetal calf serum DMEM/RPMI1640/McCoy ' 5a culture medium, in 37 DEG C, 5%CO2In incubator
Culture, changes the liquid once for 2~3 days, and logarithmic growth phase cell is for testing.
Cell Proliferation detects (mtt assay): the cancer cell of logarithmic growth phase is made 2 × 104The suspension of a cell/mL,
Every 100 μ L of hole is added in 96 well culture plates.If reagent controls group, the experiment of tumour cell control group and various various concentration drugs
Group.Cis-platinum, lobaplatin and oxaliplatin list medicine are first separately added into tumour cell before experiment, so that cis-platinum, lobaplatin, oxaliplatin
Final concentration of 5ng/mL, 50ng/mL, 500ng/mL, 5000ng/mL, 50000ng/mL, the IC50 of three kinds of drugs is learnt with this
Concentration, is added the heparin compound of various concentration, then starts following Collaborative experiment.Test component list medicine group and drug combination
Group.Reagent controls group adds equivalent culture medium, and tumour cell control group adds the culture medium of the identical not drug containing of equivalent, each dosage 3
A parallel hole.In CO2After cultivating for 24 hours in incubator, every 10 μ L of Kong Zhongjia 0.5%MTT continues to cultivate 4h, and it is molten that 100 μ L tri- are added
Liquid is solved, is destained overnight to MTT and is completely dissolved, each hole absorbance (A), meter are measured at Yu Zidong elisa reading instrument 570nm and 630nm
Inhibiting rate and IC50.
Interpretation of result:
(1) lobaplatin and Low-molecular-weight Heparins Calcium are administered in combination:
Lobaplatin and Low-molecular-weight Heparins Calcium are administered in combination, as a result such as table 1.By analyzing as it can be seen that for liver cancer cells
Bel7402 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 1~4
138%~164%；It is right when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 4 for hepatocellular carcinoma H22
The inhibiting rate of tumour increases 122%；For pancreatic cancer cell BxPc-3, when rubbing for Low-molecular-weight Heparins Calcium in composition and lobaplatin
When you are than being 0.12~4,117%~181% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Colo357, work as group
When closing that the molar ratio of Low-molecular-weight Heparins Calcium and lobaplatin is 0.25~4 in object, 111% is increased to the inhibiting rate of tumour~
156%；For pancreatic cancer cell Capan-1, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 0.25~4,
It increases 112%~129% to the inhibiting rate of tumour；For pancreatic cancer cell Panc-1, when low molecular weight heparin in composition
When the molar ratio of calcium and lobaplatin is 2~4,108%~113% is increased to the inhibiting rate of tumour；For pancreatic cancer cell
Miapaca-2 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 3.3~5.7
Grow 116%~124%；For pancreatic cancer cell Capan-2, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is
When 0.2~5.7,109%~133% is increased to the inhibiting rate of tumour；For lung carcinoma cell A427, when low point in composition
When the molar ratio of sub- calciparine and lobaplatin is 2~4,238% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-
H1299 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 0.12~4
108%~115%；For lung carcinoma cell NCI-H2170, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 2~4
When, 268%~270% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H358, when low molecule liver in composition
When the molar ratio of plain calcium and lobaplatin is 0.12~4,118%~204% is increased to the inhibiting rate of tumour；For lung carcinoma cell
NCI-H460 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 2~4
120%；For lung cell A549, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 5~20, to tumour
Inhibiting rate increase 148%~161%；For colorectal cancer cell Colo205, when Low-molecular-weight Heparins Calcium in composition and Lip river
When the molar ratio of platinum is 0.12~4,105%~130% is increased to the inhibiting rate of tumour；For colorectal cancer cell
LoVo increases 128% to the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 4；It is right
In colorectal cancer cell RKO, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 20, to the inhibiting rate of tumour
Increase 184%；For breast cancer cell HCC1806, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 4,
It increases 145% to the inhibiting rate of tumour；For breast cancer cell MCF-7, when Low-molecular-weight Heparins Calcium in composition and lobaplatin
Molar ratio be 2~4 when, 149~156% are increased to the inhibiting rate of tumour；For breast cancer cell TD-47, work as combination
When the molar ratio of Low-molecular-weight Heparins Calcium and lobaplatin is 1~4 in object, 133~219% are increased to the inhibiting rate of tumour；For
Breast cancer cell MM-436, the inhibition when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 13.3, to tumour
Rate increases 161%；For breast cancer cell MM231, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and lobaplatin is 5.7~
When 13.3,164%~240% is increased to the inhibiting rate of tumour；For cervical cancer cell Hela, when low molecule in composition
When the molar ratio of calciparine and lobaplatin is 13.3,109% is increased to the inhibiting rate of tumour.Lobaplatin and Low-molecular-weight Heparins Calcium connection
It is as shown in table 1 to the inhibiting rate data of each tumour cell to close administration:
Table 1
(2) lobaplatin and Enoxaparin Sodium are administered in combination:
Lobaplatin and Enoxaparin Sodium are administered in combination, as a result such as table 2.By analyzing as it can be seen that for liver cancer cells
Bel7402 increases the inhibiting rate of tumour when the molar ratio of Enoxaparin Sodium in composition and lobaplatin is 0.56
118%；For pancreatic cancer cell Colo357, when the molar ratio of Enoxaparin Sodium in composition and lobaplatin is 0.28~4.4,
It increases 117%~130% to the inhibiting rate of tumour；For pancreatic cancer cell Panc-1, when Enoxaparin Sodium in composition
When molar ratio with lobaplatin is 2.2~4.4,119%~123% is increased to the inhibiting rate of tumour；For pancreatic cancer cell
Capan-2 increases the inhibiting rate of tumour when the molar ratio of Enoxaparin Sodium in composition and lobaplatin is 7.3
135%；For lung carcinoma cell A427, when the molar ratio of Enoxaparin Sodium in composition and lobaplatin is 0.56~4.3, to swollen
The inhibiting rate of tumor increases 123%~135；For lung carcinoma cell NCI-H1299, when Enoxaparin Sodium in composition and lobaplatin
When molar ratio is 0.56,121% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H2170, when in composition according to
When the molar ratio of promise heparin sodium and lobaplatin is 0.14,122% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-
H358 increases the inhibiting rate of tumour when the molar ratio of Enoxaparin Sodium in composition and lobaplatin is 0.14~0.56
119%~124%；For lung carcinoma cell NCI-H460, when the molar ratio of Enoxaparin Sodium in composition and lobaplatin is 4.4,
It increases 112% to the inhibiting rate of tumour；For lung cell A549, when mole of Enoxaparin Sodium in composition and lobaplatin
When than being 22,136% is increased to the inhibiting rate of tumour；For breast cancer cell MM231, when Enoxaparin Sodium in composition
When molar ratio with lobaplatin is 14.7,138% is increased to the inhibiting rate of tumour；For cervical cancer cell Hela, work as combination
When the molar ratio of Enoxaparin Sodium and lobaplatin is 3.6 in object, 117% is increased to the inhibiting rate of tumour.Lobaplatin and Yi Nuo liver
Plain sodium is administered in combination as shown in table 2 to the inhibiting rate of each tumour cell:
Table 2
(3) lobaplatin and Dalteparin Sodium are administered in combination:
Lobaplatin and Dalteparin Sodium are administered in combination, as a result such as table 3.By analyzing as it can be seen that for pancreatic cancer cell
Colo357 increases the inhibiting rate of tumour when the molar ratio of Dalteparin Sodium in composition and lobaplatin is 0.35~5.57
118%~133%；For pancreatic cancer cell Panc-1, when the molar ratio of Dalteparin Sodium in composition and lobaplatin is 1.39~
When 5.57,121%~133% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Capan-2, when being reached in composition
When the molar ratio of heparin sodium and lobaplatin is 0.29~9.3,107%~139% is increased to the inhibiting rate of tumour；For lung cancer
Cell A427 increases the inhibiting rate of tumour when the molar ratio of Dalteparin Sodium in composition and lobaplatin is 0.35~5.57
122~154%；For lung carcinoma cell NCI-H2170, when the molar ratio of Dalteparin Sodium in composition and lobaplatin is 2.78,
It increases 136% to the inhibiting rate of tumour；For lung carcinoma cell NCI-H358, when rubbing for Dalteparin Sodium in composition and lobaplatin
When you are than being 0.17~5.57,134%~150% is increased to the inhibiting rate of tumour；For lung cell A549, work as combination
When the molar ratio of Dalteparin Sodium and lobaplatin is 2.8~22.2 in object, 122%~136% is increased to the inhibiting rate of tumour；It is right
Suppression in colorectal cancer cell Lovo, when the molar ratio of Dalteparin Sodium in composition and lobaplatin is 0.7~2.78, to tumour
Rate processed increases 122%~128%；For breast cancer cell HCC1806, when the molar ratio of Dalteparin Sodium in composition and lobaplatin
When being 0.7 and 2.78,115% is increased to the inhibiting rate of tumour；For breast cancer cell MM-436, when reaching liver in composition
When the molar ratio of plain sodium and lobaplatin is 18.6,150% is increased to the inhibiting rate of tumour.Lobaplatin and Dalteparin Sodium are administered in combination
It is as shown in table 3 to the inhibiting rate of each tumour cell:
Table 3
(4) lobaplatin and heparin sodium are administered in combination:
Lobaplatin and heparin sodium are administered in combination, as a result such as table 4.By analyzing as it can be seen that for pancreatic cancer cell
Colo357 increases the inhibiting rate of tumour when the molar ratio of heparin sodium in composition and lobaplatin is 0.33~0.67
122%~124%；For pancreatic cancer cell Capan-1, when the molar ratio of heparin sodium in composition and lobaplatin is 0.02~0.67
When, 112%~140% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Panc-1, when in composition heparin sodium with
When the molar ratio of lobaplatin is 0.17~0.67,132%~135% is increased to the inhibiting rate of tumour；For pancreatic cancer cell
Capan-2 increases 126% to the inhibiting rate of tumour when the molar ratio of heparin sodium in composition and lobaplatin is 1.1；It is right
In lung carcinoma cell A427, when the molar ratio of heparin sodium in composition and lobaplatin is 0.02~0.67, to the inhibiting rate of tumour
Increase 143~180%；For lung carcinoma cell NCI-H1299, when the molar ratio of heparin sodium in composition and lobaplatin be 0.12 and
When 0.67,111% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H358, when heparin sodium in composition and Lip river
When the molar ratio of platinum is 0.02~0.67,126%~143% is increased to the inhibiting rate of tumour；For lung cell A549,
When the molar ratio of heparin sodium in composition and lobaplatin is 0.1~3.4,119% is increased to the inhibiting rate of tumour~
129%；It is right when the molar ratio of heparin sodium in composition and lobaplatin is 0.02~0.67 for breast cancer cell HCC1806
The inhibiting rate of tumour increases 116~126%；For breast cancer cell TD-47, when mole of heparin sodium in composition and lobaplatin
When than being 0.33~0.67,132~159% are increased to the inhibiting rate of tumour；For cervical cancer cell Hela, work as composition
When the molar ratio of middle heparin sodium and lobaplatin is 2.2,113% is increased to the inhibiting rate of tumour.Lobaplatin and heparin sodium combine to
Medicine is as shown in table 4 to the inhibiting rate of each tumour cell:
Table 4
(5) cis-platinum and Low-molecular-weight Heparins Calcium are administered in combination:
Cis-platinum and Low-molecular-weight Heparins Calcium are administered in combination, as a result such as table 5.By analyzing as it can be seen that for liver cancer cells
Bel7402 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 1.49~2.97
Grow 134%；For pancreatic cancer cell BxPc-3, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 7.42~
When 14.83,120%~126% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Colo357, when low in composition
When the molar ratio of molecular heparin calcium and cis-platinum is 7.42~14.83,135%~138% is increased to the inhibiting rate of tumour；It is right
It is right when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 1.49~2.97 in pancreatic cancer cell Miapaca-2
The inhibiting rate of tumour increases 131%~134%；For pancreatic cancer cell Capan-2, when in composition Low-molecular-weight Heparins Calcium with
When the molar ratio of cis-platinum is 3.71~14.83,120%~143% is increased to the inhibiting rate of tumour；For lung carcinoma cell
A427 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 1.85~7.41
191~229%；For lung carcinoma cell NCI-H1299, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 2.47
When with 9.88,124% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H2170, when low molecule liver in composition
When the molar ratio of plain calcium and cis-platinum is 4.94~9.88,116% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-
H460 increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 3.71~7.41
175~176%；For lung cell A549, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 3.71~
When 29.65,400%~967% is increased to the inhibiting rate of tumour；For colorectal cancer cell Colo205, when in composition
When the molar ratio of Low-molecular-weight Heparins Calcium and cis-platinum is 0.93~14.83,132%~153% is increased to the inhibiting rate of tumour；
It is right when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 14.85~29.7 for colorectal cancer cell Lovo
The inhibiting rate of tumour increases 226~240%；For breast cancer cell HCC1806, when in composition Low-molecular-weight Heparins Calcium with it is suitable
When the molar ratio of platinum is 7.4,135% is increased to the inhibiting rate of tumour；For breast cancer cell TD-47, when in composition
When the molar ratio of Low-molecular-weight Heparins Calcium and cis-platinum is 1.49~2.97,132%~138 is increased to the inhibiting rate of tumour；It is right
In breast cancer cell MM-436, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 7.42~14.83, to swollen
The inhibiting rate of tumor increases 151%~159；For breast cancer cell MM231, when Low-molecular-weight Heparins Calcium in composition and cis-platinum
When molar ratio is 14.85~29.7,244%~322% is increased to the inhibiting rate of tumour；For cervical cancer cell Hela,
When the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 29.7,126% is increased to the inhibiting rate of tumour.Low point
Sub- calciparine is very weak to the cytotoxicity to most tumour cells, this shows the antitumor work of Low-molecular-weight Heparins Calcium itself
With almost without or it is very weak.Cis-platinum and Low-molecular-weight Heparins Calcium are administered in combination as shown in table 5 to the inhibiting rate of each tumour cell:
Table 5
(6) cis-platinum and Enoxaparin Sodium are administered in combination:
Cis-platinum and Enoxaparin Sodium are administered in combination, as a result such as table 6.By analyzing as it can be seen that for cervical cancer cell
Hela increases the inhibiting rate of tumour when the molar ratio of Low-molecular-weight Heparins Calcium in composition and cis-platinum is 0.26~1.04
121~131%.In the concentration range of measurement, Enoxaparin Sodium does not all show any cell to all tumour cells
Toxic action.
Table 6
(7) cis-platinum and Dalteparin Sodium are administered in combination:
Cis-platinum and Dalteparin Sodium are administered in combination, as a result such as table 7.For pancreatic cancer cell Miapaca-2, work as combination
When the molar ratio of Dalteparin Sodium and cis-platinum is 1.05~4.2 in object, 109%~114% is increased to the inhibiting rate of tumour；It is right
The inhibiting rate of tumour is increased when the molar ratio of Dalteparin Sodium in composition and cis-platinum is 42 in lung cell A549
218%；For colorectal cancer cell Colo205, when the molar ratio of Dalteparin Sodium in composition and cis-platinum is 0.22~0.88,
It increases 112%~121% to the inhibiting rate of tumour；For colorectal cancer cell HF-29, when in composition Dalteparin Sodium with
When the molar ratio of cis-platinum is 0.26~2.1,152~274% are increased to the inhibiting rate of tumour；For cervical cancer cell
Hela increases 114% to the inhibiting rate of tumour when the molar ratio of Dalteparin Sodium in composition and cis-platinum is 0.33.?
In the concentration range of measurement, Dalteparin Sodium does not all show any cytotoxicity to all tumour cells.
Table 7
(8) cis-platinum and heparin sodium are administered in combination:
Cis-platinum and heparin sodium are administered in combination, as a result such as table 8.By analyzing as it can be seen that for liver cancer cells
Bel7402 increases the inhibiting rate of tumour when the molar ratio of heparin sodium in composition and cis-platinum is 0.25~0.5
110%~114%；For hepatocellular carcinoma H22, when the molar ratio of heparin sodium in composition and cis-platinum is 2.5, to tumour
Inhibiting rate increase 125%；For pancreatic cancer cell Colo357, when the molar ratio of heparin sodium in composition and cis-platinum is 2.5
When, 111% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Panc-1, when heparin sodium in composition and cis-platinum
When molar ratio is 0.5,113% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Miapaca-2, when in composition
When the molar ratio of heparin sodium and cis-platinum is 0.25~0.5,109% is increased to the inhibiting rate of tumour；For lung carcinoma cell
A427, when the molar ratio of heparin sodium in composition and cis-platinum is 125~2.5,125 is increased to the inhibiting rate of tumour~
157%；It is right when the molar ratio of heparin sodium in composition and cis-platinum is 0.21 and 0.84 for lung carcinoma cell NCI-H1299
The inhibiting rate of tumour increases 131%；For lung carcinoma cell NCI-H460, when the molar ratio of heparin sodium in composition and cis-platinum is
When 0.63~1.25,125~130% are increased to the inhibiting rate of tumour；For colorectal cancer cell Colo205, work as combination
When the molar ratio of heparin sodium and cis-platinum is 0.01~0.05 in object, 132% is increased to the inhibiting rate of tumour；For breast cancer
Cell MM231 increases 129% to the inhibiting rate of tumour when the molar ratio of heparin sodium in composition and cis-platinum is 5；It is right
In cervical cancer cell Hela, when the molar ratio of heparin sodium in composition and cis-platinum is 0.625~5, to the inhibiting rate of tumour
Increase 114%~122%.In the concentration range of measurement, heparin sodium is not almost all shown all tumour cells carefully
Cytotoxicity.
Table 8
(9) oxaliplatin and Low-molecular-weight Heparins Calcium are administered in combination:
Oxaliplatin and Low-molecular-weight Heparins Calcium are administered in combination, as a result such as table 9.By analyzing as it can be seen that for liver cancer
Cell Bel7402, the inhibition when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 16~64, to tumour
Rate increases 223%；For pancreatic cancer cell BxPc-3, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is
When 8~64,154%~163% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Miapaca-2, when in composition
When the molar ratio of Low-molecular-weight Heparins Calcium and oxaliplatin is 16~64,307%~319% is increased to the inhibiting rate of tumour；
For pancreatic cancer cell Capan-2, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 0.5~64,
142%~308% is increased to the inhibiting rate of tumour；For lung carcinoma cell A427, when Low-molecular-weight Heparins Calcium in composition and Austria
When the molar ratio of husky benefit platinum is 8~64,180%~263% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-
H2170, the inhibition when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 1.35~21.55, to tumour
Rate increases 224%~314%；For lung carcinoma cell NCI-H358, when Low-molecular-weight Heparins Calcium in composition and oxaliplatin
When molar ratio is 8~64,200%~251% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H460, work as group
When closing that the molar ratio of Low-molecular-weight Heparins Calcium and oxaliplatin is 4~64 in object, 161% is increased to the inhibiting rate of tumour~
224%；It is right when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 4~64 for lung cell A549
The inhibiting rate of tumour increases 212%~266%；For colorectal cancer cell Colo205, when Low-molecular-weight Heparins Calcium in composition
When molar ratio with oxaliplatin is 5.39~43.10,137%~154% is increased to the inhibiting rate of tumour；It is straight for tying
Colon-cancer cell Lovo, the inhibition when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 8~64, to tumour
Rate increases 190%~321%；For colorectal cancer cell RKO, when rubbing for Low-molecular-weight Heparins Calcium in composition and oxaliplatin
When you are than being 1~64,117%~140 is increased to the inhibiting rate of tumour；For breast cancer cell MCF-7, when in composition
When the molar ratio of Low-molecular-weight Heparins Calcium and oxaliplatin is 8~64,158%~231% is increased to the inhibiting rate of tumour；It is right
In breast cancer cell TD-47, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 8~64, to tumour
Inhibiting rate increase 220%~242%；For breast cancer cell MM-436, when Low-molecular-weight Heparins Calcium in composition and Austria are husky
When the molar ratio of sharp platinum is 8~64,166%~173% is increased to the inhibiting rate of tumour；For breast cancer cell MM231,
When the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 8~64,163% is increased to the inhibiting rate of tumour
~181%；For cervical cancer cell Hela, when the molar ratio of Low-molecular-weight Heparins Calcium in composition and oxaliplatin is 16~64
When, 297%~303% is increased to the inhibiting rate of tumour.In the concentration range of overwhelming majority measurement, Low-molecular-weight Heparins Calcium
Cytotoxicity is not all shown to almost all of tumour cell.
Table 9
(10) oxaliplatin and Enoxaparin Sodium are administered in combination inhibiting rate:
Oxaliplatin and Enoxaparin Sodium are administered in combination, as a result such as table 10.By analyzing as it can be seen that for cancer of pancreas
Cell BxPc-3, when the molar ratio of Enoxaparin Sodium in composition and oxaliplatin is 0.5~64, to the inhibiting rate of tumour
Increase 111%~127%；For pancreatic cancer cell Capan-2, when mole of Enoxaparin Sodium in composition and oxaliplatin
When than being 0.5~32,189%~267% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H358, work as combination
When the molar ratio of Enoxaparin Sodium and oxaliplatin is 16~64 in object, 111% is increased to the inhibiting rate of tumour~
144%；For lung carcinoma cell NCI-H460, when the molar ratio of Enoxaparin Sodium in composition and oxaliplatin is 8~64,
115%~144% is increased to the inhibiting rate of tumour；For colorectal cancer cell Colo205, when low molecular weight heparin in composition
When the molar ratio of calcium and lobaplatin is 0.5,123% is increased to the inhibiting rate of tumour；For colorectal cancer cell Lovo, work as group
When closing that the molar ratio of Enoxaparin Sodium and oxaliplatin is 0.5~8 in object, 146% is increased to the inhibiting rate of tumour~
157；For breast cancer cell MM-436, when the molar ratio of Enoxaparin Sodium in composition and oxaliplatin is 0.5~64,
113%~166% is increased to the inhibiting rate of tumour；For breast cancer cell MM231, when Enoxaparin Sodium in composition and Austria
When the molar ratio of husky benefit platinum is 64,115% is increased to the inhibiting rate of tumour.In the concentration range of measurement, Enoxaparin
Sodium does not almost all show cytotoxicity to all tumour cells.
Table 10
(11) oxaliplatin and Dalteparin Sodium are administered in combination:
Oxaliplatin and Dalteparin Sodium are administered in combination, as a result such as table 11.By analyzing as it can be seen that for liver cancer cells
Bel7402 increases the inhibiting rate of tumour when the molar ratio of Dalteparin Sodium in composition and oxaliplatin is 644
163%；For pancreatic cancer cell BxPc-3, when the molar ratio of Dalteparin Sodium in composition and oxaliplatin is 0.5~64,
110%~120% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Miapaca-2, when in composition Dalteparin Sodium with
When the molar ratio of oxaliplatin is 64,177% is increased to the inhibiting rate of tumour；For pancreatic cancer cell Capan-2, work as group
When closing that the molar ratio of Dalteparin Sodium and oxaliplatin is 0.5~32 in object, 186% is increased to the inhibiting rate of tumour~
229%；For lung carcinoma cell A427, when the molar ratio of Dalteparin Sodium in composition and oxaliplatin is 64, to tumour
Inhibiting rate increases 174%；For lung carcinoma cell NCI-H460, when the molar ratio of Dalteparin Sodium in composition and oxaliplatin is
When 16~64,138%~173% is increased to the inhibiting rate of tumour.In most concentration ranges of measurement, dalteparinSodium
Sodium does not all show cytotoxicity to all tumour cells.
Table 11
(12) oxaliplatin and heparin sodium are administered in combination:
Oxaliplatin and heparin sodium are administered in combination, as a result such as table 12.By analyzing as it can be seen that for liver cancer cells
Bel7402 increases 142% to the inhibiting rate of tumour when the molar ratio of heparin sodium in composition and oxaliplatin is 64；
Suppression for pancreatic cancer cell Miapaca-2, when the molar ratio of heparin sodium in composition and oxaliplatin is 64, to tumour
Rate processed increases 205%；For lung carcinoma cell NCI-H2170, when the molar ratio of heparin sodium in composition and oxaliplatin is
When 2.22,141% is increased to the inhibiting rate of tumour；For colorectal cancer cell RKO, when heparin sodium in composition and Austria are husky
When the molar ratio of sharp platinum is 1.66~6.65,133%~138% is increased to the inhibiting rate of tumour；For breast cancer cell
TD-47 increases the inhibiting rate of tumour when the molar ratio of heparin sodium in composition and oxaliplatin is 6.65~13.3
121~142%.In most concentration ranges of measurement, heparin sodium is not almost all shown all tumour cells carefully
Cytotoxicity.
Table 12
The present invention is investigated platinum class chemical combination in addition to investigating the inhibiting rate of platinum-like compounds and heparin compound drug combination
Object is administered alone the inhibiting rate being administered alone to the inhibiting rate and heparin-like compounds of tumour to tumour.Due to being administered alone
Inhibiting rate is significantly not so good as drug combination, so, excessive description is not done to the inhibiting rate being administered alone in the method for the present invention.
(13) platinum-like compounds are administered alone inhibiting rate, as shown in table 13:
Table 13
(14) Enoxaparin Sodium is administered alone inhibiting rate, as a result as shown in table 14: table 14
(15) Dalteparin Sodium is administered alone inhibiting rate, as a result as shown in Table 15:
Table 15
(16) heparin sodium is administered alone inhibiting rate, as a result as shown in table 16:
Table 16
Platinum-like compounds and heparin-like compounds are combined by the present invention, and are applied to and are prepared in anti-tumor drug.Two
The dosage that can reduce platinum medicine is used in combination in person, and the antitumous effect after combination is more preferable；The two combination can be improved
Sensibility of the tumour cell to platinum medicine；Platinum-like compounds type is different, and the antitumous effect of composition is different；Heparin class
Species difference is closed, the antitumous effect of composition is different；The combination of both platinum-like compounds and heparin-like compounds exists certain
Dose relationship.
The present invention has also been attempted except hepatoma cell strain noted in the disclosure, pancreas cancer cell strain, lung cancer cell line, knot
Rectum cancer cell strain, breast carcinoma cell strain, outside cervical cancer cell lines, the classification of other cell strains and specific type also all generate
The effect of certain inhibition tumour；The present invention has also been attempted the platinum-like compounds in addition to lobaplatin, cis-platinum and oxaliplatin,
It is combined combination with heparin-like compounds, produces the effect that certain enhancing inhibits tumour；The present invention, which has also been attempted, to be divided
Heparin-like compounds except sub- calciparine, Enoxaparin Sodium, Dalteparin Sodium and heparin sodium, from different platinum-like compounds into
Row is administered in combination, and can enhance antitumous effect；The present invention also attempts the composition by platinum-like compounds and heparin-like compounds
It is combined with conventional anticancer compound, antitumous effect can be further increased.
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical scheme and beneficial effects
It describes in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in guarantor of the invention
Within the scope of shield.
Claims (6)
1. the composition of a kind of platinum-like compounds and heparin-like compounds, which is characterized in that the composition includes platinum class chemical combination
Object and heparin-like compounds.
2. the composition of a kind of platinum-like compounds and heparin-like compounds according to claim 1, which is characterized in that described
The molar ratio of heparin-like compounds and the platinum-like compounds is 0.005~64；The platinum-like compounds are cis-platinum, lobaplatin and Austria
One of husky benefit platinum is a variety of；The heparin-like compounds are Low-molecular-weight Heparins Calcium, Enoxaparin Sodium, Dalteparin Sodium and heparin
One of sodium is a variety of.
3. the composition of a kind of platinum-like compounds and heparin-like compounds according to claim 2, which is characterized in that described
It is 0.12~20 to form that composition, which is Low-molecular-weight Heparins Calcium and lobaplatin with molar ratio,；
Or it is 0.14~22.2 to form that the composition, which is Enoxaparin Sodium and lobaplatin with molar ratio,；
Or it is 0.17~22.2 to form that the composition, which is Dalteparin Sodium and lobaplatin with molar ratio,；
Or it is 0.02~3.4 to form that the composition, which is heparin sodium and lobaplatin with molar ratio,；
Or it is 0.02~29.7 to form that the composition, which is Low-molecular-weight Heparins Calcium and cis-platinum with molar ratio,；
Or it is 0.03~33.33 to form that the composition, which is Enoxaparin Sodium and cis-platinum with molar ratio,；
Or it is 0.03~42 to form that the composition, which is Dalteparin Sodium and cis-platinum with molar ratio,；
Or it is 0.005~5 to form that the composition, which is heparin sodium and cis-platinum with molar ratio,；
Or it is 0.5~64 to form that the composition, which is molecular heparin calcium and oxaliplatin with molar ratio,；
Or it is 0.5~64 to form that the composition, which is Enoxaparin Sodium and oxaliplatin with molar ratio,；
Or it is 0.5~64 to form that the composition, which is Dalteparin Sodium and oxaliplatin with molar ratio,；
Or it is 0.5~64 to form that the composition, which is heparin sodium and oxaliplatin with molar ratio,.
4. according to claim 1~3 prepared by the composition of a kind of described in any item platinum-like compounds and heparin-like compounds
Application in anti-tumor drug.
5. the composition of a kind of platinum-like compounds according to claim 4 and heparin-like compounds is preparing anti-tumor drug
In application, it is described antitumor in anti-liver cancer and anti-, anti-pancreatic cancer, anti-lung cancer, anti-colorectal carcinoma, anti-breast cancer and anti-cervical cancer
It is one or more.
6. the composition of a kind of platinum-like compounds according to claim 4 and heparin-like compounds is preparing anti-tumor drug
In application, which is characterized in that in preparation and the application in the anti-tumor drug of conventional anticancer drugs conjunctive use.
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