CN101513528A - Compound chemotherapy medicament for treating liver cancer and multi-drug resistance tumor - Google Patents
Compound chemotherapy medicament for treating liver cancer and multi-drug resistance tumor Download PDFInfo
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- CN101513528A CN101513528A CNA2008100263603A CN200810026360A CN101513528A CN 101513528 A CN101513528 A CN 101513528A CN A2008100263603 A CNA2008100263603 A CN A2008100263603A CN 200810026360 A CN200810026360 A CN 200810026360A CN 101513528 A CN101513528 A CN 101513528A
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- arteannuin
- glutathion
- artemisine
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Abstract
The invention discloses medicinal application of a compound chemotherapy medicament of artemisinins (dihydroartemisinin, artemisinin succinate, artemisinin methyl ether, or artemisinin ethyl ether), glutathione depleting agents (diethyl maleate, N-ethyl-maleimide or buthionine sulfoximine) and antioxidant enzyme inhibitors (mercapto-succinic acid and 3-amino-triazole), wherein the compound chemotherapy medicament can be used as the compound chemotherapy medicament for liver cancer and multi-drug resistance tumor with efficient, quick effect, low toxicity and low cost. Liver cancer and multi-drug resistance tumor patients orally take the medicament or are applied by intravenous injection; the everyday treatment dosage comprises 1 to 100 milligrams per kilogram of the dihydroartemisinin, the artemisinin succinate, the artemisinin methyl ether or the artemisinin ethyl ether, 1 to 80 millimoles per kilogram of the diethyl maleate, the N-ethyl-maleimide or the buthionine sulfoximine, 1 to 50 milligrams per kilogram of the mercapto-succinic acid, and 1 to 50 milligrams per kilogram of the 3-amino-triazole; the medicament can be used once or repeatedly; and after the treatment, the tumor can disappear or the proliferation of the tumor can be controlled, so the patients can live for a long time and work normally.
Description
Technical field
The invention belongs to the biological medicine technology field, particularly relate to artemisine, glutathion depletor and the polyphenoils enzyme inhibitor compound recipe chemotherapeutics for the treatment of hepatocarcinoma and multi-drug resistance tumor.
Background technology
Malignant tumor is the 2nd big fatal disease that is only second to cardiovascular and cerebrovascular disease.According to World Health Organization's 1996 annual reports, global tumor new cases are up to 9,000,000, and wherein China falls ill 1,600,000.According to another American Cancer Society's statistics, global number because of cancer stricken death was 6,700,000 in 2002, and to the year two thousand twenty, this numeral will reach 1,030 ten thousand.The sickness rate of hepatocarcinoma is in world's umber one among China male, and per 100,000 philtrums have 36.7 people.The optimal treatment method of hepatocarcinoma is a surgical resection, but because the liver cancer patient early symptom is not obvious, add that the hepatoma carcinoma cell blood supply is abundant, make that propagation, the progress of most hepatocarcinoma are faster than the tumor of other internal organs, and easily form portal vein tumor thrombus, cause hepatocarcinoma hematogenous spread and transfer and relapse, generally only have 20% patient to obtain the surgical engine meeting, and most of liver cancer patient is being made a definite diagnosis death in later six months.Because existing chemotherapeutics generally lacks specificity and targeting, liver cancer patient is carried out general system chemotherapy, and not only toxic and side effects is serious, and curative effect is disappointing, and systemic chemotherapy can not really improve the survival rate of liver cancer patient worse.Simultaneously, along with being extensive use of and the appearance of thing followed multi-drug resistance phenomenon of chemotherapeutic, tumor is more and more lower to the sensitivity of chemotherapeutic, and the antitumor action of some chemotherapeutic descends day by day, causes patient's treatment rate and survival rate further to reduce.The chemotherapy of tumors medicine of demanding developing new targeting and low toxic and side effects at present urgently and overcoming multi-drug resistance is arranged in view of that.
Since reported first arteannuin such as Woerdenbag in 1993 had cytotoxicity to the Ehrlich tumor cell, arteannuin was at leukemia (IC
50=1.11 μ mol/L), colon cancer (IC
50=2.13 μ mol/L) etc. the effectiveness in non-entity and the entity tumor is verified.Our research is also found, but arteannuin succinate specificity liver cancer apoptosis reducing obtains to confirm by Electronic Speculum imaging and flow cytometry.Arteannuin is as the characteristics of chemotherapy of tumors medicine: (1) is to the targeting sexual assault of tumor cell: the fast breeding of tumor cell makes it efficiently express transferrins and receptor thereof and ferrum that can the enrichment high concentration, and arteannuin just with its unique peroxide bridge structure with ferrum reaction generation carbon radicals and bring into play the tumor-killing effect.Liver is the abundantest organ of whole body iron content, and it not only has abundant hemoglobin (containing haemachrome is iron porphyrin), and a large amount of ferruginous bilirubin and cytochrome are arranged, thereby more helps artemisine the orientation of leukemia and tumor cell of liver is killed and wounded; (2) toxic and side effects is low: arteannuin antineoplastic action mechanism mainly is inducing apoptosis of tumour cell, can not disturb Normocellular biosynthesis and metabolic process, thereby toxicity is very low.In addition, secular malaria clinical observation proves that also arteannuin does not have obvious toxic and side effects; (3) no cross resistance: artemisinin action is rapid, is difficult for induced mbc, and the artemisinin action target spot is different fully with other antitumor drug, thereby the tumor of anti-other chemotherapeutic and anti-arteannuin.In vitro study finds that also arteannuin can be blocked the vascularization of Kaposi and suppress its growth, shows that arteannuin can also cause it because of hungry dead rapidly by the blood supply of blocking-up tumor cell.
, over year, arteannuin is not used clinically as the antineoplastic agent of main flow surplus in the of 10, and main cause is that arteannuin is easily destroyed by the nonprotein sulfhydryl compound of high concentration in the body especially reduced glutathion (GSH).Owing to fail to solve this difficult problem for a long time, cause arteannuin to be difficult to bring into play the antitumor action of quick-acting, targeting, low toxicity.Studies show that in a large number radiosensitizer fourth Guang sulfenimide (BSO) can suppress γ-glutathione synthetase activity, the biosynthesis of blocking-up GSH improves the sensitivity of tumor to radiotherapy.We discover that ethyl maleate. (molecular weight 172.18) and N-ethyl maleimide micromolecular compounds such as (molecular weight 125.12) also can make the GSH in the tumor cell exhaust.Utilize this class glutathion depletor can eliminate the destruction of GSH, thereby improve the anti-tumor activity of arteannuin, especially promote arteannuin the lethality of tumor in vivo to arteannuin.On the other hand, why multi-drug resistance tumor can produce multi-drug resistance, and except that the effect of Teat pipette, most important reason is that the content of its detoxification system composition GSH is higher than other tumor cells, more is higher than normal tissue cell.This shows that the glutathion depletor can not only significantly reduce the multi-drug resistance of tumor, and the anti-tumor activity of arteannuin is had sensitization.
Arteannuin is antioxidase in the easy inducing tumor cell (mainly being a glutathion peroxidase and catalase) expression of gene as another weak point of chemotherapy of tumors medicine, thereby offsets the lethal effect of arteannuin carbon radicals to tumor.Therefore, specificity antioxidation application of enzyme inhibitors can be eliminated the cancellation effect of antioxidase to arteannuin.We confirm by experiment, can significantly improve the lethality of arteannuin to tumor by the activities of antioxidant enzymes that reduces tumor as the mercapto succinic acid (having another name called mercaptosuccinic acid .) and the 3-aminotriazole(ATA) of glutathion peroxidase and hydrogen peroxide enzyme inhibitor.
We select for use artemisine, glutathion depletor and antioxidase inhibitor to form the compound recipe chemotherapeutics, are used for the clinical treatment of hepatocarcinoma and multi-drug resistance tumor.Artemisine in the compound recipe can combine with abundant ferrum in the cancerous cell and produce the high concentration carbon free radical, thus performance targeting therapy for tumor effect.Simultaneously, the angiogenesis of arteannuin checks and acts on the inhibition that reaches glutathione S-transferase, also helps to improve arteannuin pressing down of cancerous cell killed effect; Glutathion depletor in the compound recipe can be removed the especially GSH in the multi-drug resistance tumor cell of cancerous cell, makes its lethal effect to artemisine responsive more, helps to reduce the toleration of tumor cell to chemotherapeutic.Ethyl maleate. and N-ethyl maleimide can make GSH exhaust at short notice, but can go up after the drug withdrawal, and its toxicity is very low; Antioxidase inhibitor in the compound recipe can reduce glutathion peroxidase and catalatic vigor respectively, thereby reduces the arteannuin carboxylic free radical effect forfeiture that these antioxidases cause, and further improves the tumor-killing effect.More than 3 medicine couplings the advantage that each medicine possessed is combined, make it to kill the effect of tumor cell with the performance of different separately mechanism.
By the test in tumor cell of liver strain and tumor animal, this compound recipe shows good dispersing tumor and prognosis effect, and toxic and side effects is very low, might be developed to hepatocarcinoma evident in efficacy and multi-drug resistance tumor medicine, will fill up the blank of present hepatocarcinoma and multi-drug resistance tumor chemotherapeutic.
Summary of the invention
Artemisine of the present invention is native compound and the synthesis of derivatives with arteannuin mother nucleus structure, comprises dihydroarteannuin, arteannuin succinate, Artemtherin or arteannuin ether.
Described glutathion depletor comprises ethyl maleate., N-ethyl maleimide or fourth Guang sulfenimide.
Described antioxidase inhibitor comprises mercapto succinic acid and 3-aminotriazole(ATA).
Comprise hepatocarcinoma and multi-drug resistance tumor therapeutic use in the quality standard of described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics and/or the package insert.
Comprise hepatocarcinoma and multi-drug resistance tumor in the clinical indication of described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics.
When described artemisine and glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics treatment hepatocarcinoma and multi-drug resistance tumor patient, artemisine is that arteannuin, dihydroarteannuin, arteannuin succinate, Artemtherin or arteannuin ether dosage are 1-100mg/kg/d, ethyl maleate., N-ethyl maleimide or fourth Guang sulfenimide dosage are 1-80mmol/kg/d, mercapto succinic acid and 3-aminotriazole(ATA) dosage respectively are 1-50mg/kg/d, can divide 1 time or repeatedly use.
The specific embodiment
Artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics can effectively be treated hepatocarcinoma and multi-drug resistance tumor by following therapeutic scheme.
Embodiment 1
For body weight is adult liver cancer patient or anti-other chemotherapeutics patient of 50-80kg, take medicine every day 1 time, serve on for 4 weeks, the dosage of the contained dihydroartemisinine of pill, arteannuin succinate, arteannuin ether or Artemtherin is 200mg, the dosage of ethyl maleate., N-ethyl maleimide or fourth Guang sulfenimide is 80mmol, and the dosage of mercapto succinic acid and 3-aminotriazole(ATA) respectively is 20mg and 50mg.Teenage patient's medication reduces by half or follows the doctor's advice.
Embodiment 2
For body weight is adult liver cancer patient or anti-other chemotherapeutics patient of 50-80kg, quiet weekly notes 2 times, 4 weeks of logotype, the dosage of the contained dihydroartemisinine of medicament, arteannuin succinate, arteannuin ether or Artemtherin is 300mg, the dosage of ethyl maleate., N-ethyl maleimide or fourth Guang sulfenimide is 100mmol, and mercapto succinic acid and 3-aminotriazole(ATA) respectively are 30mg and 60mg.Teenage patient's medication reduces by half or follows the doctor's advice.
Claims (9)
1, artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics treatment hepatocarcinoma and multi-drug resistance tumor.
2, purposes according to claim 1 is characterized in that described artemisine is some native compounds and the semi-synthetic derivant that contains the arteannuin mother nucleus structure, comprises dihydroarteannuin, arteannuin succinate, Artemtherin or arteannuin ether.
3 purposes according to claim 1 is characterized in that described glutathion depletor comprises ethyl maleate., N-ethyl maleimide or fourth Guang sulfenimide.
4, purposes according to claim 1 is characterized in that described antioxidase inhibitor is mercapto succinic acid and 3-aminotriazole(ATA).
5, purposes according to claim 1 is characterized in that comprising hepatocarcinoma and multi-drug resistance tumor therapeutic use in the quality standard of described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics and/or the package insert.
6, purposes according to claim 1 is characterized in that comprising hepatocarcinoma and multi-drug resistance tumor in the clinical indication of described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics.
7, purposes according to claim 1, when it is characterized in that described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics treatment hepatocarcinoma and multi-drug resistance tumor patient, wherein the dosage of dihydroarteannuin, arteannuin succinate, Artemtherin or arteannuin ether is 1-100mg/kg/d, can 1 time or repeatedly use.
8, purposes according to claim 1, when it is characterized in that described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics treatment hepatocarcinoma and multi-drug resistance tumor patient, wherein the dosage of ethyl maleate., N-ethyl maleimide or fourth Guang sulfenimide is 1-80mmol/kg/d, can 1 time or repeatedly use.
9, purposes according to claim 1, when it is characterized in that described artemisine, glutathion depletor and antioxidase inhibitor compound recipe chemotherapeutics treatment hepatocarcinoma and multi-drug resistance tumor patient, wherein the dosage of mercapto succinic acid and 3-aminotriazole(ATA) respectively is 1-50mg/kg/d, can 1 time or repeatedly use.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100263603A CN101513528A (en) | 2008-02-18 | 2008-02-18 | Compound chemotherapy medicament for treating liver cancer and multi-drug resistance tumor |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008100263603A CN101513528A (en) | 2008-02-18 | 2008-02-18 | Compound chemotherapy medicament for treating liver cancer and multi-drug resistance tumor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106177951A (en) * | 2016-08-26 | 2016-12-07 | 首都师范大学 | A kind of composite of photothermal deformation nanomaterial loadings artemisinin-based drug and preparation method and application |
| CN110251684A (en) * | 2019-07-05 | 2019-09-20 | 中国药科大学 | Have nano-complex of the oxidative stress from enlarging function, preparation method and application |
-
2008
- 2008-02-18 CN CNA2008100263603A patent/CN101513528A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106177951A (en) * | 2016-08-26 | 2016-12-07 | 首都师范大学 | A kind of composite of photothermal deformation nanomaterial loadings artemisinin-based drug and preparation method and application |
| CN106177951B (en) * | 2016-08-26 | 2020-05-22 | 首都师范大学 | Composite material with artemisinin drugs loaded on photo-thermal conversion nano material and preparation method and application thereof |
| CN110251684A (en) * | 2019-07-05 | 2019-09-20 | 中国药科大学 | Have nano-complex of the oxidative stress from enlarging function, preparation method and application |
| CN110251684B (en) * | 2019-07-05 | 2021-10-29 | 中国药科大学 | Nano compound with oxidative stress self-amplification function, preparation method and application |
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Open date: 20090826 |