Weber G, Natsumeda Y, Pillwein K
Adv Enzyme Regul. 1985;24:45-65. doi: 10.1016/0065-2571(85)90069-x.
The molecular correlation concept proposed that IMP dehydrogenase activity should be a sensitive target of chemotherapy. This hypothesis received support from an array of evidence. IMP dehydrogenase has the lowest activity in purine biosynthesis; it is the rate-limiting enzyme in GTP production; the enzymic activity is transformation-and progression-linked; it is elevated in all examined animal and human neoplastic cells. The activity of GMP synthetase and the concentrations of GMP and dGTP were increased in cancer cells. Whereas guanine salvage has a high potential activity, the low guanine content may well curtail actual salvage capacity. Ribonucleotide reductase activity was two orders of magnitude lower than that of IMP dehydrogenase. Tiazofurin, a C-nucleoside, had marked cytotoxicity on hepatoma cells in vitro and was the first drug that as a single agent profoundly inhibited the proliferation of the subcutaneously inoculated solid hepatoma 3924A in the rat. The impact of tiazofurin administration in hepatoma cells was revealed in a cascade of biochemical alterations involving primary, secondary and tertiary targets and markers of this drug action. The primary target was IMP dehydrogenase where the active metabolite of tiazofurin, TAD, was thought to be absorbed to the NADH site of the enzyme. As a consequence, the enzymic activity declined rapidly to about 30-40% and returned to normal range by 36 to 48 hr after injection. The secondary targets and markers are the profoundly decreased pools of guanylates (GMP, GDP, GTP). Concurrently, the concentrations of IMP and PRPP were increased 8- to 15-fold. The elevated IMP pools were attributed to the de-inhibition of the AMP deaminase activity subsequent to the decline in GTP concentration. The rise in PRPP pools was attributed to the selective inhibition of GPRT and HPRT activities by the high IMP pool which did not affect APRT activity. This interpretation is supported by the 6- to 8-fold increase in the concentrations of guanine and hypoxanthine and the lack of change in the adenine pools inthe hepatomas after tiazofurin administration. The marked drop in NAD concentration which was drug dose- and time-dependent is attributed to the competition for NAD pyrophosphorylase activity by the precursors of NAD and tiazofurin monophosphate. The tertiary targets were dominated by the profound alterations in the concentrations of the dNTPs. This was characterized by a rapid and persistent drop (for 3 days) of the dGTP pool. The concentrations of dATP and dCTP also declined, but these alterations were less pronounced and the pools returned to normal after 2 days.(ABSTRACT TRUNCATED AT 400 WORDS)
分子关联概念提出，肌苷酸脱氢酶活性应是化疗的一个敏感靶点。这一假说得到了一系列证据的支持。肌苷酸脱氢酶在嘌呤生物合成中活性最低；它是鸟苷三磷酸（GTP）生成中的限速酶；酶活性与细胞转化和进展相关；在所有检测的动物和人类肿瘤细胞中其活性均升高。癌细胞中鸟苷酸合成酶的活性以及鸟苷酸（GMP）和脱氧鸟苷三磷酸（dGTP）的浓度增加。虽然鸟嘌呤补救合成具有较高的潜在活性，但低鸟嘌呤含量可能会严重限制实际的补救能力。核糖核苷酸还原酶的活性比肌苷酸脱氢酶低两个数量级。替拉扎明，一种碳核苷，在体外对肝癌细胞具有显著的细胞毒性，是第一种作为单一药物能显著抑制大鼠皮下接种的实体肝癌3924A增殖的药物。替拉扎明给药对肝癌细胞的影响体现在一系列生化改变中，涉及该药物作用的一级、二级和三级靶点及标志物。一级靶点是肌苷酸脱氢酶，替拉扎明的活性代谢产物TAD被认为结合到该酶的烟酰胺腺嘌呤二核苷酸（NADH）位点。结果，酶活性迅速下降至约30 - 40%，注射后36至48小时恢复到正常范围。二级靶点和标志物是鸟苷酸池（GMP、GDP、GTP）大幅减少。同时，肌苷酸（IMP）和5 - 磷酸核糖 - 1 - 焦磷酸（PRPP）的浓度增加8至15倍。IMP池升高归因于GTP浓度下降后腺苷酸脱氨酶活性的去抑制。PRPP池升高归因于高IMP池对鸟嘌呤磷酸核糖转移酶（GPRT）和次黄嘌呤磷酸核糖转移酶（HPRT）活性的选择性抑制，而这并不影响腺嘌呤磷酸核糖转移酶（APRT）的活性。替拉扎明给药后肝癌中鸟嘌呤和次黄嘌呤浓度增加6至8倍以及腺嘌呤池无变化支持了这一解释。烟酰胺腺嘌呤二核苷酸（NAD）浓度显著下降，且呈药物剂量和时间依赖性，这归因于NAD和替拉扎明单磷酸的前体对NAD焦磷酸化酶活性的竞争。三级靶点主要表现为脱氧核苷酸三磷酸（dNTPs）浓度的显著变化。其特征是dGTP池迅速且持续下降（持续3天）。dATP和dCTP的浓度也下降，但这些变化不太明显，2天后池恢复正常。（摘要截短至400字）
