CN102526033B - Composition prepared from epigallocatechin gallate and mitomycin C and used for suppressing tumor cell proliferation - Google Patents
Composition prepared from epigallocatechin gallate and mitomycin C and used for suppressing tumor cell proliferation Download PDFInfo
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- CN102526033B CN102526033B CN 201010587252 CN201010587252A CN102526033B CN 102526033 B CN102526033 B CN 102526033B CN 201010587252 CN201010587252 CN 201010587252 CN 201010587252 A CN201010587252 A CN 201010587252A CN 102526033 B CN102526033 B CN 102526033B
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- egcg
- epigallocatechin gallate
- ametycin
- mitomycin
- tumor cell
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Abstract
The invention belongs to the fields of medicine and gene engineering, and provides a composition for suppressing tumor cell proliferation. The composition for suppressing tumor cell proliferation comprises epigallocatechin gallate and mitomycin C serving as active ingredients and pharmaceutically necessary auxiliary materials, wherein the molar ratio of the epigallocatechin gallate to the mitomycin C is 800:1-20:1. As proved by an experiment, by using the composition prepared from the epigallocatechin gallate and the mitomycin C or using the epigallocatechin gallate during supply of the mitomycin C, the treatment effect of the mitomycin C for suppressing tumor cell proliferation can be remarkably enhanced, and the toxicity on the liver and kidney of a nude mouse is avoided basically. The epigallocatechin gallate in the active ingredients of the composition has rich resource and low price, and the treatment cost of a tumor patient can be lowered while the suppression ratio of tumors isincreased.
Description
Technical field
The invention belongs to medicine and genetic engineering field, relate to the compositions that suppresses tumor cell proliferation, relate in particular to the compositions of the inhibition tumor cell proliferation of being made by epigallocatechin gallate (EGCG) (EGCG) and ametycin (MITOMYCIN C).
Background technology
Ametycin is a kind of broad-spectrum anti-tumor antibiotic of separation and Extraction from the streptomyces caespitosus culture fluid, and multiple cancer is had antitumaous effect, and its action principle can make the DNA depolymerization of cell, hinders copying of DNA simultaneously, thereby suppresses tumour cell division.This product is cell cycle nonspecific agent (CCNSA), and its antitumor spectrum is wider, and effect is rapid, but therapeutic index is not high, and toxicity is bigger.Clinically be applicable to digestive tract cancer, as gastric cancer, intestinal cancer, hepatocarcinoma and cancer of pancreas etc., curative effect is better.Also effective to pulmonary carcinoma, breast carcinoma, cervical cancer and chorionic epithelioma etc.Also can be used for malignant lymphoma, carcinous pleural effusions and ascites.
The side effect of ametycin mainly contains: 1, bone marrow depression mainly is that leukocyte and platelet descend; 2 gastrointestinal reactions, are felt sick and vomiting etc. at inappetence, and are generally lighter; 3 injection sites can have phlebitis, as spill outside the blood vessel, can cause the tissue necrosis ulceration; Liver, renal dysfunction can appear in 4 a few patients; 5 can have stomatitis, weak and alopecia etc. sometimes.
This medicine also may disturb women's menstrual cycle and may stop mankind spermatozoon and produce, and also may injure fetus, carries out contraceptives in case of necessity really to avoid conceived.During the treatment, infected easily, please avoid come in and go out public place and preventing cold as far as possible.The sensation of stomatitis, skin ulcer and thorn thorn is easily arranged, and oral cavity cleaning needs thoroughly.
Folium Camelliae sinensis (tea, camellia sinensis) is one of beverage that is loved by the people.The whole world is annual to produce about 2,500,000 tons, and wherein 20% is that green tea, 78% is that black tea, 2% is oolong tea.Though the kind of Folium Camelliae sinensis is a lot, attract attention with the green tea behaviour.A large amount of in vitro studies and zoopery proof green tea extract have multiple biological activity and pharmacodynamics effect, as cancer-resisting, angiogenesis inhibitor, mutation, antioxidation, defying age, antibiotic, antiinflammatory, blood fat reducing, antiplatelet aggregation etc., wherein with the relation of cancer be study the most extensively, also be the most complicated significant important topic.
Main component in the green tea is tea polyphenols, account for about 30% of dry weight of tea leaves, major part is catechin in the tea polyphenols, and epigallocatechin gallate (EGCG) ((-) epigallocatechin gallate (EGCG)) content is the highest, accounts for about 80% of catechin.The EGCG molecular formula is C
22H
18O
11, molecular weight is 458.4.It is the biological anti-oxidant that a kind of high-efficiency broad spectrum has no side effect, and is commonly called as nutgall catechin gallic acid ester.Epicatechol gallate can effectively be removed and cause multiple disease and old and feeble interior free yl and peroxide, improve body immunity, slow down aging has usefulness such as excellent antiviral, blood fat reducing, fresh-keeping, beauty treatment, has been widely used in industries such as medicine, health care, food, daily use chemicals.But green tea extract is not cytotoxic drug after all, and is not obvious in external direct killing effect to tumor cell.Green tea extract and main component thereof can not replace existing antitumor drug, and its unique value is as the biochemical regulator in the chemotherapy of tumors, is expected to strengthen the anti-tumor activity of existing antitumor drug, reduces the toxicity of antitumor drug.
Up to the present, the report of the relevant EGCG of Shang Weijian and mitomycin C with C use.
Summary of the invention
The purpose of this invention is to provide a kind of compositions that suppresses tumor cell proliferation, relate in particular to the compositions of the inhibition tumor cell proliferation of being made by epigallocatechin gallate (EGCG) (EGCG) and ametycin (MITOMYCIN C).
Experiment confirm of the present invention, the compositions that epigallocatechin gallate (EGCG) (EGCG) and ametycin (MITOMYCIN C) are made, or when giving ametycin (MITOMYCIN C), unite and use epigallocatechin gallate (EGCG) can significantly improve the therapeutic effect that ametycin suppresses tumor cell proliferation.
The compositions of inhibition tumor cell proliferation of the present invention comprises adjuvant necessary on active component and the pharmaceutics, it is characterized in that described active component is following material: 1) epigallocatechin gallate (EGCG), 2) ametycin; The mol ratio of described epigallocatechin gallate (EGCG) and ametycin is 800:1-20:1.
Among the present invention, its molecular formula of described epigallocatechin gallate (EGCG) is C
22H
18O
11, molecular weight is 458.4.EGCG is available from Sigma company, article No. 50299, English full name: ()-cis-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1 (2H)-benzopyran-3,5,7-triol 3-gallate, ()-cis-3,3 ', 4 ', 5,5 ', 7-Hexahydroxy-flavane-3-gallate, EGCG; CAS number: 989-51-5.MDL number: MFCD00075940.
Among the present invention, described ametycin (Mitomycin C) is antifol, available from Sigma(article No. M0503).Common name: full name Mitomycin C from Streptomyces caespitosus.Molecular structure is as follows.
。
The CAS of ametycin number: 50-07-7, molecular formula: C15H18N4O5; Molecular weight t:334.33;
The Beilstein accession number:7231816;
MDL number:MFCD00078109.
Among the present invention, the compositions of making that contains EGCG and ametycin is used for tumor cell (for example, hepatoma cell strain SK-Hep1), the result shows, compares with only using ametycin, and the effect that suppresses tumor cell proliferation obviously strengthens.The use of described compositions can obviously reduce the independent use amount of ametycin, and it is more obvious along with the increase of EGCG consumption that it reduces effect.
Among the present invention, the compositions of EGCG and ametycin is used for the transplanted tumor in nude mice model, and the result shows, compares with only using ametycin, compositions of the present invention significantly strengthens the inhibition of transplanted tumor in nude mice growth, and effect is better than rapamycin and ametycin compositions.Simultaneously, detection is that the poisonous effect of medicine after the administration of index shows with the body weight change, when EGCG and mitomycin C with C are used the nude mice body weight is not obviously influenced, and described compositions does not have toxicity substantially to liver and the kidney of nude mice, and rapamycin and mitomycin C with C use then have than high toxicity liver and the kidney of nude mice.
Among the present invention, adopt described compositions to compare test with using EGCG or ametycin separately, the result shows that described compositions is suppressing to have obvious synergistic effect aspect the growth of tumour cell, and potentiation has EGCG and ametycin Concentraton gradient effect.Enumerated EGCG in the embodiments of the invention and ametycin content mol ratio is respectively 40:3,100:1,200:1,120:1,160:1,200:3,80:1,32:1, etc., experiment shows, is that the scope of 400:1-20:1 all is resultful at both content.
A kind of method of killing tumor cell also is provided among the present invention, and it comprises step: add EGCG and ametycin compositions in tumor cell, the mol ratio of EGCG and ametycin is 400:1-20:1.
Described tumor cell can be SK-Hep1, QGY-7703, SMMC7721, Hep3B, HepG2, Focus, Huh7, L02 or PLC cell.
Cell used in the present invention is all enough in ATCC.
Compositions of the present invention when when (administration) used in treatment, can provide different effects.Usually, but these materials are formulated in nontoxic, inertia with pharmaceutically acceptable aqueous carrier medium in, wherein pH is about 7-8 usually, although pH value can change to some extent with being formulated Substance Properties and disease to be treated.The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
Compositions with EGCG of the present invention and ametycin is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains protein and pharmaceutically acceptable carrier or the excipient for the treatment of effective dose.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.EGCG of the present invention and ametycin can be made into the injection form, for example are prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.In addition, EGCG of the present invention also can use with the other treatment agent with the compositions of ametycin.
Among the present invention, the compositions of EGCG and ametycin can be injection or tablet.
When the compositions of EGCG of the present invention and ametycin is used as medicine, can with the treatment effective dose this medicament administration in mammal, wherein should the treatment effective dose in usually at least about 50 milligrams of EGCG/ kg body weight.The conventional usage and dosage of ametycin: quiet notes, adult 4mg～6mg/ time 1～2 time/week, measures 40mg～60mg the course for the treatment of.Oral, 2mg～6mg/ day, total amount 100mg～150mg were 1 course for the treatment of.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
The present invention has following outstanding advantage:
The invention provides a kind of new compositions that contains EGCG and ametycin.Said composition can be used for preparing antitumor drug.Can obviously strengthen the antitumous effect of ametycin, reduce consumption and the medicine cost of ametycin simultaneously relatively.
Because the EGCG in the present composition is natural Folium Camelliae sinensis extract, and Folium Camelliae sinensis is the frequent drinking beverage of population in the whole world 2/3rds.Not only aboundresources is cheap, has passed through drinking more than thousand, does not almost have toxic and side effects.In the suppression ratio that improves tumor, reduced the treatment cost of tumor patient.
The specific embodiment
Embodiment 1The synergy of EGCG and ametycin
EGCG and ten kinds of medicines resistant to liver cancer are united use and all had cooperative effect, and are wherein very remarkable with the synergy of ametycin in the SK-Hep1 cell.Present embodiment has further been verified the coupling effect of EGCG and ametycin, and result's proof CI value in certain concentration range all has synergism less than 1, two kind of medicine.The result shows that EGCG and mitomycin C with C use can improve the antitumous effect of ametycin.
Table 1
Embodiment 2EGCG and ametycin have cooperative effect
The fixing concentration of EGCG in ten kinds of hepatoma cell line is with the mitomycin C with C medication.Adopt following Jin Shi formula Q-value to estimate the coupling effect.
Q=Ea+b/(Ea+Eb-Ea×Eb)
Wherein, Ea+b is the drug combination suppression ratio, and Ea and Eb are respectively the suppression ratio of A medicine and B medicine;
Two medicines that molecule represents actual measurement merge suppression ratio, and denominator is that expectation merges suppression ratio.
The Q=0.85-1.15 scope is represented simple addition, and the Q=1.15-2 scope represents enhancing is arranged, Q〉obviously enhancing of 2 expressions, Q＜0.55-0.85 represents that antagonistic effect is arranged, the Q＜obvious antagonism of 0.55 expression.
The result shows that EGCG and ametycin all have certain synergy in specific cell strain, illustrates that EGCG can strengthen the anti-tumor activity of existing medicines resistant to liver cancer in specific cell strain.
The drug combination effect Q-value of table 2 EGCG and Mitomycin C
| ? | Mitomycin C |
| SMMC7721 | 0.786483 |
| HepG2 | 1.031289 |
| QGY | 0.953553 |
| SK-Hep1 | 1.533545 |
| YY1 | 1.098953 |
| Huh7 | 0.91549 |
| Hep3B | 1.094528 |
| L02 | 1.159277 |
| Focus | 0.967784 |
| PLC | 1.011517 |
In order to verify above experimental result, further use the method for geometric ratio coupling, use CI(combination index) value estimates the coupling effect.CI=D
1/ D
X1+ D
2/ D
X2+ α D
1D
2/ D
X1D
X2, D wherein
1, D
2Be two medicines, two medicines desired concns separately when producing the X effect when share, D
X1, D
X2Be two prescriptions, two medicines concentration separately when producing the X effect when solely using.α=0 is two kinds of mutual repellency medicines, and α=1 is two kinds of mutual nonexclusion medicines.CI＜1 is synergism; CI=1 is summation action; CI〉1 be antagonism.In the SK-Hep1 cell, ametycin and the coupling of EGCG geometric ratio, the result shows that the CI value is all less than 1 in certain concentration range.Illustrate that Q-value is consistent with CI value evaluation effect, in the SK-Hep1 cell, all have cooperative effect when EGCG and ametycin coupling.
Embodiment 3EGCG can the potentiation ametycin, reduces the consumption of ametycin
In the SK-Hep1 cell with the ametycin of 0.25,0.5,0.75 μ M respectively with the EGCG coupling of 10,20,30,40,50 μ M, can meet or exceed the effect that 1 μ M ametycin uses separately after the EGCG coupling of the ametycin of 0.25,0.5,0.75 μ M and variable concentrations.According to the software statistics analysis, unite with EGCG and to use that needed ametycin amount reduces along with the increase of EGCG amount when reaching the half inhibition, and have the Concentraton gradient effect.Above experimental result explanation EGCG and mitomycin C with C are used, and can effectively strengthen the antitumous effect of ametycin and reduce its consumption.
Embodiment 4During the bare mouse different species growth of xenografted of EGCG to the toxic and side effects of body
The BALB/C-nu/nu nude mice was raised for 4 week-6 weeks under no-special pathogen (SPF) condition.The SK-hep-1 cell is got 3 * 10
6Be injected at the oxter, right side of nude mice.After the tumor body forms, matched group intraperitoneal injection of saline every day; The sodium carboxymethyl cellulose group oral normal saline that contains 0.5% sodium carboxymethyl cellulose every day; Sorafenib group dosage is 60 mg/kg body weight/day, and is oral; EGCG group dosage is 25 mg/kg body weight/day or 50 mg/kg body weight/day, lumbar injection.The SK-hep-1 nude mice model is total to administration 13 days.
The influence of the nude mice body weight of 1, EGCG
The variation of nude mice body weight is an index of chemotherapeutics toxicity.The situation of change of nude mice body weight can be done an evaluation intuitively to the toxicity of medicine in the xenotransplantation tumor model of detection SK-hep-1 cell.The result shows that 25 mg/kg EGCG and the nude mice body weight of 50 mg/kg EGCG do not have influence substantially, illustrate that toxic and side effects is lower; The positive control Sorafenib does not have influence substantially to the nude mice body weight yet.
The nude mice liver of 2, EGCG, nephrocardiac toxicity
By detecting glutamate pyruvate transaminase (ALT) and glutamic oxaloacetic transaminase, GOT (AST) content, blood urea nitrogen (BUN) creatinine (CREA) and cholesterol (CHO1) content, observation hepar damnification, the situation of kidney injury and heart and injury.The result shows that in SK-hep-1 transplanted tumor model, Sorafenib is bigger to nude mice liver, nephrocardiac damage; 25 mg/kg EGCG and the nude mice liver of 50 mg/kg EGCG, kidney and heart then do not have toxicity substantially.
The influence of the nude mice liver of table 3 EGCG, kidney and cardiac toxicity
Claims (9)
1. a compositions that suppresses tumor cell proliferation comprises adjuvant necessary on active component and the pharmaceutics, it is characterized in that described active component is following material: 1) epigallocatechin gallate (EGCG), 2) ametycin; The mol ratio of described epigallocatechin gallate (EGCG) and ametycin is 800:1～20:1.
2. the compositions of inhibition tumor cell proliferation as claimed in claim 1 is characterized in that, the mol ratio of epigallocatechin gallate (EGCG) and ametycin is 200:1～40:1.
3. compositions as claimed in claim 1 is characterized in that, the mol ratio of epigallocatechin gallate (EGCG) and ametycin is 120:1～40:1.
4. compositions as claimed in claim 1 is characterized in that, the mol ratio of epigallocatechin gallate (EGCG) and ametycin is 100:1～40:1.
5. the compositions of inhibition tumor cell proliferation as claimed in claim 1 is characterized in that, its molecular formula of described epigallocatechin gallate (EGCG) is C
22H
18O
11, molecular weight is 458.4.
6. the application of the described compositions of claim 1 in the preparation antitumor drug.
7. application as claimed in claim 6 is characterized in that, described tumor is hepatocarcinoma.
8. application as claimed in claim 6 is characterized in that, adds the described compositions of claim 1 in the tumor cell of In vitro culture.
9. application as claimed in claim 8 is characterized in that, described tumor cell is SMMC7721, HepG2, QGY, SK-Hep1, YY1, Huh7, Hep3B, L02, Focus or PLC cell.
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|---|---|---|---|---|
| CN1444935A (en) * | 2002-05-09 | 2003-10-01 | 华东理工大学 | Application of Epigallocatechin gallate (EGCG) in anti-tumor medicine |
| CN101507730A (en) * | 2009-03-26 | 2009-08-19 | 复旦大学 | Combination of epigallocatechin-3-gallate and cerubidin and use thereof |
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| CN1444935A (en) * | 2002-05-09 | 2003-10-01 | 华东理工大学 | Application of Epigallocatechin gallate (EGCG) in anti-tumor medicine |
| CN101507730A (en) * | 2009-03-26 | 2009-08-19 | 复旦大学 | Combination of epigallocatechin-3-gallate and cerubidin and use thereof |
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