STUDY ON EFFECTIVE COMBINATION AND ENHANCED EFFECTS OF ANTICANCERDRUGS

1.为了阐明抗癌联合化疗的疗效，我们采用高效液相色谱法分析了药物的胞内活性代谢产物，以及这些药物对核酸代谢的影响。经甲氨蝶呤治疗后，细胞内ATP、GTP、dTTP和dCTP水平下降。当Ara-CTP浓度高于dCTP时，Ara-C对细胞生长有显著影响。因此，dCTP/Ara-CTP比值是影响Ara-C细胞毒性的重要因素之一。甲氨蝶呤可增加细胞内FUTP和Ara-CTP的产生。这些增强的效果是基于每一组中的生化调节。VP16和Ara-C联合化疗具有相似的调节作用。6TG代谢为6-硫代GMP、GDP、GTP。然而，6MP的主要产物是6-硫代IMP。检测到少量的6-硫代GMP，但不产生6-硫代GDP、GTP。经6TG和6MP处理后，细胞内ATP池和GTP池水平下降。细胞内dCTP和dTTP池在暴露于6TG后有所下降，而在6MP时未见下降。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。蛋白激酶C和佛波二酯受体与多药耐药有关。佛波酯也与糖皮质激素诱导的生长抑制有关。

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.