Rowinsky E K, Windle J J, Von Hoff D D
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229-3272, USA.
J Clin Oncol. 1999 Nov;17(11):3631-52. doi: 10.1200/JCO.1999.17.11.3631.
Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most critical-modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
Ras蛋白是鸟嘌呤核苷酸结合蛋白，在正常细胞和转化细胞生长的控制中起关键作用，是过去十年中研究最为深入的蛋白之一。在受到各种生长因子和细胞因子刺激后，Ras激活多种下游效应器，包括Raf-1/丝裂原活化蛋白激酶途径和Rac/Rho途径。在大约30%的人类癌症中，包括相当比例的胰腺和结肠腺癌，突变的ras基因产生的突变蛋白保持在活性状态，从而传递不受控制的增殖信号。Ras经历几种翻译后修饰，这些修饰有助于其附着在质膜的内表面。第一个也是最关键的修饰是在一种由蛋白法尼基转移酶（FTase）催化的反应中添加一个法尼基类异戊二烯部分。因此，抑制FTase将阻止Ras成熟为其生物活性形式，并且FTase作为潜在的治疗靶点备受关注。已经鉴定出不同类别的FTase抑制剂，它们可阻断Ras的法尼基化，逆转人类细胞系中Ras介导的细胞转化，并抑制裸鼠中人类肿瘤细胞的生长。在患有既定肿瘤的转基因小鼠中，FTase抑制剂可使一些肿瘤消退，这似乎是通过细胞凋亡和细胞周期调控介导的。FTase抑制剂在动物研究中耐受性良好，并且不会像大多数传统抗癌药物那样在正常组织中产生普遍的细胞毒性作用，而这是传统抗癌药物的一个主要局限性。目前正在对FTase抑制剂进行临床评估，以确定按照在临床前研究中预示最佳治疗指数的剂量方案给药的可行性。由于FTase独特的生物学特性，设计针对疾病的II期和III期疗效评估面临巨大挑战。
