CN102526081A - Medicinal composition capable of inhibiting proliferation of tumor cells - Google Patents
Medicinal composition capable of inhibiting proliferation of tumor cells Download PDFInfo
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- CN102526081A CN102526081A CN2010105965629A CN201010596562A CN102526081A CN 102526081 A CN102526081 A CN 102526081A CN 2010105965629 A CN2010105965629 A CN 2010105965629A CN 201010596562 A CN201010596562 A CN 201010596562A CN 102526081 A CN102526081 A CN 102526081A
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- egcg
- doxorubicin
- doxorubicine
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Abstract
The invention belongs to the fields of medicines and gene engineering and provides a medicinal composition capable of inhibiting proliferation of tumor cells. The medicinal composition comprises gallocatechin epicatechol gallate and doxorubicine which serve as active ingredients and necessary pharmaceutical auxiliary materials, wherein the molar ratio of the gallocatechin epicatechol gallate to the doxorubicine is (400:1) to (20:1). Tests prove that the composition prepared from the gallocatechin epicatechol gallate and the doxorubicine, or prepared by combining the doxorubicine with the gallocatechin epicatechol gallate can obviously improve the curative effect of the doxorubicine of inhibiting proliferation of the tumor cells. The medicinal composition basically does not have toxicity to livers and kidneys of nude mice; and the gallocatechin epicatechol gallate in the active ingredients is rich in resources and low in price, so the tumor inhibition ratio is increased and the treatment cost of tumor patients is reduced.
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 that contains epigallocatechin gallate (EGCG) (EGCG) and amycin (Doxorubicin).
Background technology
Amycin, promptly (Doxorubicin ADM), calls: doxorubicin, hydroxyl rubidomycin, doxorubicin, ADR Adriamycin.Amycin is a kind of AGPM, can suppress the synthetic of RNA and DNA, and the strongest to the inhibitory action of RNA, antitumor spectra is wider, and kinds of tumors is all had effect, belongs to cell cycle nonspecific agent (CCNSA), and the tumor cell of various growth cycles is all had killing action.Mainly be applicable to acute leukemia, all effective to acute lymphoblastic leukemia and granulocyte leukemia, generally as the second line medicine, promptly when the choice drug drug resistance, can consider to use this medicine.Malignant lymphoma can be used as the at first medicine that is used alternatingly.These article are the broad-spectrum anti-tumor medicine, can produce biochemical effect widely to body, have intensive cytotoxic effect.Its mechanism of action mainly is these article intercalation of DNA and suppress the synthetic of nucleic acid.Be used to treat acute lymphoblastic leukemia, acute myeloblastic leukemia, He Jiejin and non Hodgkin lymphoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, nephroblastoma, neuroblastoma, bladder tumor, thyroid tumor, chorionic epithelioma, carcinoma of prostate, carcinoma of testis, gastric cancer, hepatocarcinoma etc. clinically.
Main toxic reaction has, leukocyte and thrombocytopenia, and about 60% ~ 80% patient can be taken place; 100% patient has alopecia in various degree, can recover growth after the drug withdrawal; Cardiac toxicity shows as arrhythmia, and ST-T changes, and has more 1 ~ 6 month after the present drug withdrawal, uses vitamin B6 and coenzyme Q10 early and can lower its toxicity to heart; Nauseating, loss of appetite; Medicine overflows outside the blood vessel can cause tissue ulcer and necrosis.In addition, redness can appear in urine after the medication.
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; Like cancer-resisting, angiogenesis inhibitor, mutation, antioxidation, defying age, antibiotic, antiinflammatory, blood fat reducing, antiplatelet aggregation or the like, wherein be with the relation of cancer study the most extensively, also be the most complicated significant important topic.
Main component in the green tea is a tea polyphenols; Account for about 30% of dry weight of tea leaves; Major part is a 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 now, relevant EGCG of Shang Weijian and Doxorubicin unite the report of 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 that contains epigallocatechin gallate (EGCG) (EGCG) and amycin (Doxorubicin).
Experiment confirm of the present invention; The compositions that epigallocatechin gallate (EGCG) (EGCG) and Doxorubicin (amycin) process, or when giving Doxorubicin (amycin), unite and use epigallocatechin gallate (EGCG) can significantly improve the therapeutic effect that Doxorubicin 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) Doxorubicin; The mol ratio of described epigallocatechin gallate (EGCG) and Doxorubicin is 400:1-20:1.
Among the present invention, its molecular formula of described epigallocatechin gallate (EGCG) is C
22H
18O
11, molecular weight is 458.4, can obtain through the market sale approach.For example, EGCG of the present invention 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 Doxorubicin common name: amycin; Doxorubicin is DNA, rna synthesis inhibitor.Amycin for example of the present invention is available from Sigma company, and article No. is D1515.Relevant parameter is following:
CAS number: 25316-40-9
Empirical?Formula?(Hill?Notation):?C
27H
29NO
11?·?HCl
Molecular weight: 579.98
Beilstein number of registration: 4229251
EC number: 246-818-3
MDL number: MFCD00077757.
Among the present invention, the compositions of processing that contains EGCG and Doxorubicin is used for tumor cell (for example, hepatoma cell strain SK-Hep1), the result shows, compares with only using Doxorubicin, and the effect that suppresses tumor cell proliferation obviously strengthens.The use of said compositions can obviously reduce the independent use amount of Doxorubicin, 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 Doxorubicin is used for the transplanted tumor in nude mice model, and the result shows, compares with only using Doxorubicin; Compositions of the present invention significantly strengthens the inhibition effect of transplanted tumor in nude mice growth, and effect is superior to rapamycin and Doxorubicin compositions.Simultaneously; Detection is that the poisonous effect of medicine after the administration of index shows with the body weight change; EGCG and Doxorubicin unite when using the not obviously influence of nude mice body weight; And described compositions does not have toxicity basically to liver and the kidney of nude mice, and rapamycin and Doxorubicin unite use then to be had than high toxicity liver and the kidney of nude mice.
Among the present invention; Adopt described compositions to carry out comparative test with using EGCG or Doxorubicin 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 Doxorubicin Concentraton gradient effect.Enumerated EGCG in the embodiments of the invention and Doxorubicin content mol ratio is respectively 20:1,100:1,200:1, or the like, 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: in tumor cell, add EGCG and Doxorubicin compositions, the mol ratio of EGCG and Doxorubicin is 400:1-20:1.
Described tumor cell can be the SK-Hep1 cell.
Cell used in the present invention is all available from ATCC.
Compositions of the present invention when in treatment, using (administration), can provide different effects.Usually, can these materials are formulated in nontoxic, the inert and pharmaceutically acceptable aqueous carrier medium, wherein pH is about 7-8 usually, although pH value can be with being changed to some extent by preparation Substance Properties and disease to be treated.The pharmaceutical composition for preparing can carry out administration through conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
Compositions with EGCG of the present invention and Doxorubicin is an example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This type pharmaceutical composition contains protein and the pharmaceutically acceptable carrier or the excipient of treating effective dose.This type 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 Doxorubicin can be made into the injection form, for example prepare through conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can prepare through 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 Doxorubicin.
Among the present invention, the compositions of EGCG and Doxorubicin can be injection or tablet.
When the compositions of EGCG of the present invention and Doxorubicin is used as medicine, can wherein should treat in the effective dose with this medicament administration of treating effective dose in mammal usually at least about 50 milligrams of EGCG/ kg body weight.Per three weeks once, and are certain with the 60-75mg/m2 administration, and concrete dosage is factor such as considered route of administration, patient health situation also, and these all are within the skilled practitioners skill.
The invention provides a kind of new compositions that contains EGCG and Doxorubicin.Said composition can be used for preparing antitumor drug.Can obviously strengthen the antitumous effect of Doxorubicin, reduce consumption and the medicine cost of Doxorubicin 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 Doxorubicin
In the SK-hep-1 cell, the synergy of EGCG and Doxorubicin is more remarkable.Fixedly the concentration of Doxorubicin is 0.05 μ M, and it is 1,5,10,15,20 that EGCG adopts concentration, wherein effect best for being 0.05:20, the result sees the following form.
Present embodiment has further been verified the coupling effect of EGCG and Doxorubicin, 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 Doxorubicin unite the antitumous effect that use can improve Doxorubicin.
Table 1
| ? | Doxorubicin drug level (uM) | EGCG drug level (uM) | Doxorubicin is single with suppression ratio (%) | Doxorubicin-EGCG coupling suppression ratio (%) |
| SK-hep-1 | 0.05 | 20 | 60.75 | 73.7 |
Embodiment 2EGCG and Doxorubicin have cooperative effect
The fixing concentration of EGCG in five kinds of tumor cell lines is with the Doxorubicin drug combination.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;
On behalf of two medicines of actual measurement, molecule 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 representes enhancing is arranged, Q>obviously enhancing of 2 expressions, < 0.55-0.85 representes that antagonistic effect is arranged to Q, Q < the obvious antagonism of 0.55 expression.
The result shows that EGCG and Doxorubicin all have certain synergy in specific cell strain, explains 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 Doxorubicin
| ? | Doxorubicin |
| SK-Hep1 | 1.252831 |
| YY1 | 0.932059 |
| L02 | 0.963316 |
| Focus | 0.986501 |
| PLC | 1.023065 |
In order to verify above experimental result, further use the method for geometric ratio coupling, estimate the coupling effect with CI (combination index) value.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.< 1 is synergism to CI; CI=1 is a summation action; CI>1 be antagonism.In the SK-Hep1 cell, Doxorubicin and the coupling of EGCG geometric ratio, the result shows that the CI value is all less than 1 in certain concentration range.Explain that Q-value is consistent with CI value evaluation effect, in the SK-Hep1 cell, all have cooperative effect when EGCG and Doxorubicin coupling.
Embodiment 3EGCG during to the bare mouse different species growth of xenografted 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-Hep1 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.SK-Hep1 cell nude mice model is total to administration 13 days.
1, EGCG is to the influence of nude mice body weight
The variation of nude mice body weight is the toxic index of chemotherapeutics.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-Hep1 cell.The result shows that 25 mg/kg EGCG and 50 mg/kg EGCG do not have influence basically to the nude mice body weight, explain that toxic and side effects is lower; The positive control Sorafenib does not have influence basically to the nude mice body weight yet.
2, EGCG is to nude mice liver, nephrocardiac toxicity
Through 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-Hep1 transplanted tumor model, Sorafenib is bigger to nude mice liver, nephrocardiac damage; 25 mg/kg EGCG and 50 mg/kg EGCG then do not have toxicity basically to nude mice liver, kidney and heart.
Table 3 EGCG is to the influence of nude mice liver, kidney and cardiac toxicity
Claims (7)
1. a pharmaceutical composition 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) amycin; The mol ratio of described epigallocatechin gallate (EGCG) and amycin is 400:1-20:1.
2. the compositions of inhibition tumor cell proliferation as claimed in claim 1 is characterized in that, the mol ratio of described epigallocatechin gallate (EGCG) and amycin is 400:1～100:1.
3. compositions as claimed in claim 1 is characterized in that, the mol ratio of described epigallocatechin gallate (EGCG) and amycin is 400:1～200:1.
4. the application of the described compositions of claim 1 in the preparation antitumor drug.
5. application as claimed in claim 4 is characterized in that described tumor is a hepatocarcinoma.
6. one kind is suppressed the method that tumor cell increases, and it is characterized in that, in tumor cell, adds the said compositions of claim 1.
7. method as claimed in claim 8 is characterized in that, described tumor cell is the SK-Hep-1 cell.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109745333A (en) * | 2017-11-06 | 2019-05-14 | 深圳市龙华区人民医院 | A kind of pharmaceutical composition and its application for bladder cancer treatment |
| CN113018357A (en) * | 2021-02-08 | 2021-06-25 | 湖南农业大学 | Application of tea polyphenol and palbociclib combination in preparation of preparation for treating breast cancer |
-
2010
- 2010-12-20 CN CN2010105965629A patent/CN102526081A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 林晓贞等: "EGCG逆转人耐药肝癌细胞株多药耐药的体内实验研究", 《广西医科大学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109745333A (en) * | 2017-11-06 | 2019-05-14 | 深圳市龙华区人民医院 | A kind of pharmaceutical composition and its application for bladder cancer treatment |
| CN109745333B (en) * | 2017-11-06 | 2021-05-28 | 深圳市龙华区人民医院 | Pharmaceutical composition for treating bladder cancer and application thereof |
| CN113018357A (en) * | 2021-02-08 | 2021-06-25 | 湖南农业大学 | Application of tea polyphenol and palbociclib combination in preparation of preparation for treating breast cancer |
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Application publication date: 20120704 |