Jayaram H N, Murayama K, Pillwein K, Zhen W, Weber G
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
Cancer Chemother Pharmacol. 1992;31(2):93-6. doi: 10.1007/BF00685093.
Tiazofurin is an oncolytic nucleoside analog that has shown therapeutic activity in end-stage acute non-lymphocytic leukemia and in chronic granulocytic leukemia in blast crisis. Tiazofurin is anabolized to the active metabolite, TAD, which inhibits IMP dehydrogenase activity, leading to a reduction in guanylate pools and to the cessation of neoplastic cell proliferation. The drug exhibits potent cytostatic and cytotoxic activity against hepatoma 3924A cells in culture. In growth-inhibition and clonogenic assays, the 50% inhibitory concentration of tiazofurin was 3.8 and 4.2 microM, respectively. Dipyridamole, an inhibitor of nucleoside transport, curtails the salvage of nucleosides and bases for nucleotide biosynthesis. Dipyridamole exhibited cytotoxicity against hepatoma 3924A cells, with an LC50 of 24 microM and an IC50 of 29 microM being recorded. A combination of tiazofurin and dipyridamole provided synergistic cytotoxicity in hepatoma 3924A cells in culture. This synergistic activity was dependent on the order of addition of the drugs. Simultaneous addition of the two drugs produced antagonism, whereas preincubation of cells with tiazofurin or dipyridamole followed by addition of the second drug resulted in synergy. TAD concentrations were significantly higher (129% and 135%) in cells that had been pretreated with tiazofurin or dipyridamole before the addition of the second agent as compared with cells that had been treated simultaneously (113%). These studies indicate the importance of the order of the addition of drugs to obtain a synergistic response in combination chemotherapy and suggest the need for a careful selection of drug modulation in clinical trials of tiazofurin and dipyridamole.
硫唑嘌呤是一种溶瘤核苷类似物，已在晚期急性非淋巴细胞白血病和慢性粒细胞白血病急变期显示出治疗活性。硫唑嘌呤被代谢为活性代谢物TAD，它抑制肌苷酸脱氢酶活性，导致鸟苷酸池减少并使肿瘤细胞增殖停止。该药物在培养中对肝癌3924A细胞表现出强大的细胞生长抑制和细胞毒活性。在生长抑制和克隆形成试验中，硫唑嘌呤的50%抑制浓度分别为3.8和4.2微摩尔。双嘧达莫是一种核苷转运抑制剂，可减少核苷和碱基用于核苷酸生物合成的补救。双嘧达莫对肝癌3924A细胞表现出细胞毒性，记录的半数致死浓度（LC50）为24微摩尔，半数抑制浓度（IC50）为29微摩尔。硫唑嘌呤和双嘧达莫联合使用在培养的肝癌3924A细胞中产生协同细胞毒性。这种协同活性取决于药物添加顺序。同时添加两种药物产生拮抗作用，而先用硫唑嘌呤或双嘧达莫预处理细胞后再添加第二种药物则产生协同作用。与同时处理的细胞（113%）相比，在添加第二种药物之前先用硫唑嘌呤或双嘧达莫预处理的细胞中TAD浓度显著更高（分别为129%和135%）。这些研究表明在联合化疗中获得协同反应时药物添加顺序的重要性，并提示在硫唑嘌呤和双嘧达莫的临床试验中需要仔细选择药物调节。
