STUDY ON EFFECTIVE COMBINATION AND ENHANCED EFFECTS OF ANTICANCERDRUGS

抗癌药物有效组合及增效研究

• 批准号: 60440050
• 负责人: SAKURAI Minoru
• 金额: $ 11.01万
• 依托单位: MIE UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1985
• 资助国家: 日本
• 起止时间: 1985 至 1988
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-60440050/
• 关键词: Nucleic acid metabolism; Intracellular active metabolite; Protein Kinase C; Phorbor esters; 多剤耐性; Biochemical modulation; Collateral sensitivity; プロティンキナーゼC; ホルボールエステルレセプター; 高速液体クロマトグラフィ; MTX-5FU併用療法; 6MP,6TG; ara-C; 抗癌剤; 耐性克服; 併用療法; 高速液体ク

1. To clarify the therapeutic efficacy of anticancer combination chemotherapy, we analyzed intracellular active metabolites of drugs, and effects of these drugs on nucleic acid metabolism with high performance liquid chromatography. After treatment with methotrexate, reduction of intracelluar ATP, GTP, dTTP and dCTP levels were observed. Ara-C had significant effects on the growth of cells at the higher level of ara-CTP than of dCTP. So the dCTP/ara-CTP ratio is one of very important factors in ara-C cytotoxicity. The increased production of intracellular fluoro-UTP(FUTP) and ara-CTP by pretreatment with MTX were recognized. These enhanced effects were based on biochemical modulation in each grugs. VP16 and Ara-C combination chemotherapy showed similar modulation effects. 6TG was metabolized to 6-thioGMP, GDP, GTP. Major products of 6MP, however, was 6-thioIMP. Small quantity of 6-thioGMP was detected, but no 6-thioGDP, GTP were produced. The intracellular levels of ATP and GTP pools decreased after treatment with 6TG and 6MP. Intracellular dCTP, and dTTP pools have declined after exposure to 6TG, whereas not decline with 6MP. These results suggested that cytotoxic mechanism of 6TG include inhibition of both purine pathway and DNA synthesis and 6MP only inhibits purine pathway.2. Protein kinase C and phorbor diester receptor were related with pleiotropic drug resistance. Phorbor esters, also, were linked to the glucocorticoid-induced growth inhibition.

1.为了明确抗癌联合化疗的疗效，我们采用高效液相色谱分析了药物的细胞内活性代谢物以及这些药物对核酸代谢的影响。甲氨蝶呤治疗后，观察到细胞内 ATP、GTP、dTTP 和 dCTP 水平降低。 ara-CTP 水平高于 dCTP 时，Ara-C 对细胞生长有显着影响。因此dCTP/ara-CTP比值是ara-C细胞毒性的重要因素之一。通过MTX预处理，细胞内氟-UTP(FUTP)和ara-CTP的产量增加已得到认可。这些增强的效果基于每种药物的生化调节。 VP16和Ara-C联合化疗表现出相似的调节作用。 6TG代谢为6-thioGMP、GDP、GTP。然而，6MP的主要产物是6-thioIMP。检测到少量6-thioGMP，但不产生6-thioGDP、GTP。 6TG和6MP处理后细胞内ATP和GTP池水平下降。细胞内 dCTP 和 dTTP 池在暴露于 6TG 后有所下降，而暴露于 6MP 后则没有下降。这些结果表明，6TG的细胞毒作用机制包括抑制嘌呤途径和DNA合成，而6MP仅抑制嘌呤途径。 2．蛋白激酶C和佛硼二酯受体与多效性耐药相关。佛硼酯也与糖皮质激素诱导的生长抑制有关。

项目成果

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