White M W, Riscoe M K, Ferro A J
Biochim Biophys Acta. 1983 Jun 2;762(3):405-13. doi: 10.1016/0167-4889(83)90005-8.
The antiproliferative effects of 5'-methylthioadenosine and the 5'-methylthioadenosine analogs, 5'-isobutylthioadenosine, 5'-deoxyadenosine and 5'-methylthiotubercidin were examined using two mouse cell lines, one 5'-methylthioadenosine phosphorylase-deficient the other containing 5'-methylthioadenosine phosphorylase. All of the compounds were found to be growth inhibitory to both cell lines, demonstrating that these compounds need not be degraded to exert their inhibitory effects. A correlation was observed between the potency of the growth inhibitory effect and the ability of the cells to degrade these compounds. 5'-Methylthioadenosine, 5'-deoxyadenosine and 5'-isobutylthioadenosine, all of which are substrates for the 5'-methylthioadenosine phosphorylase in vitro, were more growth inhibitory to the 5'-methylthioadenosine phosphorylase-deficient cells than to the 5'-methylthioadenosine phosphorylase-containing cells, whereas, the 7-deaza analog, 5'-methylthiotubercidin, a nondegradable inhibitor of the 5'-methylthioadenosine phosphorylase, was a more potent inhibitor of the 5'-methylthioadenosine phosphorylase-containing cell line. Due to the inhibition by 5'-methylthiotubercidin on 5'-methylthioadenosine phosphorylase in vitro the disposition of cellularly-synthesized 5'-methylthioadenosine was explored using both cell types. 5'-Methylthiotubercidin inhibited the accumulation of exogenous 5'-methylthioadenosine from 5'-methylthioadenosine phosphorylase-deficient cells with no effect on intracellular 5'-methylthioadenosine. In contrast, 5'-methylthiotubercidin caused a large accumulation of extracellular 5'-methylthioadenosine with a concomitant smaller increase intracellularly in 5'-methylthioadenosine phosphorylase-containing cells. That cellularly-synthesized 5'-methylthioadenosine as well as the cellular excretion of this nucleoside are altered in response to treatment with 5'-methylthiotubercidin suggests two possible sites at which 5'-methylthiotubercidin may exert its effect.
使用两种小鼠细胞系检测了5'-甲硫基腺苷及其类似物5'-异丁硫基腺苷、5'-脱氧腺苷和5'-甲硫基杀结核菌素的抗增殖作用，一种细胞系缺乏5'-甲硫基腺苷磷酸化酶，另一种含有5'-甲硫基腺苷磷酸化酶。发现所有这些化合物对两种细胞系均有生长抑制作用，表明这些化合物无需降解即可发挥其抑制作用。观察到生长抑制作用的效力与细胞降解这些化合物的能力之间存在相关性。5'-甲硫基腺苷、5'-脱氧腺苷和5'-异丁硫基腺苷在体外均是5'-甲硫基腺苷磷酸化酶的底物，它们对缺乏5'-甲硫基腺苷磷酸化酶的细胞的生长抑制作用比对含有5'-甲硫基腺苷磷酸化酶的细胞更强，而7-脱氮类似物5'-甲硫基杀结核菌素是5'-甲硫基腺苷磷酸化酶的不可降解抑制剂，对含有5'-甲硫基腺苷磷酸化酶的细胞系是一种更强效的抑制剂。由于5'-甲硫基杀结核菌素在体外对5'-甲硫基腺苷磷酸化酶有抑制作用，因此使用这两种细胞类型研究了细胞合成的5'-甲硫基腺苷的代谢情况。5'-甲硫基杀结核菌素抑制了缺乏5'-甲硫基腺苷磷酸化酶的细胞中外源5'-甲硫基腺苷的积累，对细胞内5'-甲硫基腺苷没有影响。相反，5'-甲硫基杀结核菌素导致含有5'-甲硫基腺苷磷酸化酶的细胞中细胞外5'-甲硫基腺苷大量积累，同时细胞内5'-甲硫基腺苷有较小程度的增加。细胞合成的5'-甲硫基腺苷以及该核苷的细胞排泄因5'-甲硫基杀结核菌素处理而发生改变，这表明5'-甲硫基杀结核菌素可能发挥作用的两个潜在位点。
