Cysyk R L, Chisena C A, Hyman R, Monks A
Laboratory of Medicinal Chemistry, National Cancer Institute, Bethesda, MD, USA.
Cancer Lett. 1996 Dec 3;109(1-2):49-55. doi: 10.1016/s0304-3835(96)04416-3.
Tiazofurin, a clinically active anticancer agent, is undergoing additional clinical testing in combination with other agents. We found that tiazofurin is an effective biochemical modulator of 5-fluorouracil anabolism. Pretreatment of cultured L1210 cells with tiazofurin at concentrations of 1-100 microM results in an increase in the rate of conversion of 5-fluorouracil to phosphorylated metabolites. Concentrations of tiazofurin effective in increasing 5-fluorouracil anabolism cause a corresponding increase in the 5-phosphoribosyl-1-pyrophosphate pool. Studies in mice show that tiazofurin increases the lethal toxicity of 5-fluorouracil and increases the antitumor effectiveness of low doses of 5-fluorouracil: however, the combination is not more effective than an optimal dose of 5-fluorouracil given alone. These results indicate that caution should be exercised in the concurrent use of tiazofurin with other drugs, particularly 5-fluorouracil, that require 5-phosphoribosyl-1-pyrophosphate for activation or that are affected by a decrease in pyrimidine nucleotide synthesis.
硫唑嘌呤，一种临床有效的抗癌药物，正在与其他药物联合进行额外的临床试验。我们发现硫唑嘌呤是5-氟尿嘧啶合成代谢的有效生化调节剂。用浓度为1-100微摩尔的硫唑嘌呤预处理培养的L1210细胞，会导致5-氟尿嘧啶向磷酸化代谢产物的转化速率增加。有效增加5-氟尿嘧啶合成代谢的硫唑嘌呤浓度会使5-磷酸核糖-1-焦磷酸池相应增加。在小鼠身上的研究表明，硫唑嘌呤会增加5-氟尿嘧啶的致死毒性，并增加低剂量5-氟尿嘧啶的抗肿瘤效果：然而，联合使用并不比单独使用最佳剂量的5-氟尿嘧啶更有效。这些结果表明，在同时使用硫唑嘌呤与其他需要5-磷酸核糖-1-焦磷酸激活或受嘧啶核苷酸合成减少影响的药物（特别是5-氟尿嘧啶）时应谨慎。
