Kohl N E, Omer C A, Conner M W, Anthony N J, Davide J P, deSolms S J, Giuliani E A, Gomez R P, Graham S L, Hamilton K
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Nat Med. 1995 Aug;1(8):792-7. doi: 10.1038/nm0895-792.
For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.
Ras癌蛋白要转化哺乳动物细胞，必须在法尼基蛋白转移酶（FPTase）催化的反应中进行翻译后法尼基化修饰。因此，FPTase抑制剂被提议作为抗癌药物。我们发现，L-744,832模拟添加法尼基基团的CaaX基序，是一种强效且选择性的FPTase抑制剂。在患有可触及肿瘤的MMTV-v-Ha-ras小鼠中，每日给予L-744,832可导致肿瘤消退。停止治疗后，肿瘤复发，其中大多数在再次治疗时消退。对接受L-744,832治疗的小鼠进行尸检时未发现全身毒性。这种抗FPTase介导的肿瘤消退的首次证明表明，FPTase抑制剂在某些癌症中可能是安全有效的抗肿瘤药物。
