Sebti S M, Hamilton A D
Department of Oncology, University of South Florida College of Medicine, Tampa, USA.
Oncogene. 2000 Dec 27;19(56):6584-93. doi: 10.1038/sj.onc.1204146.
In 1990, more than 10 years after the discovery that the low molecular weight GTPase Ras is a major contributor to human cancer, farnesylation, a lipid posttranslational modification required for the cancer-causing activity of Ras, emerged as a major target for the development of novel anticancer agents. However, it took only 5 years from 1993, when the first farnesyltransferase inhibitors (FTIs) were reported, to 1998 when results from the first phase I clinical trials were described. This rapid progress was due to the demonstration of outstanding antitumor activity and lack of toxicity of FTIs in preclinical models. Although, many FTIs are currently in phase H and at least one is in phase III clinical trial, the mechanism of FTI antitumor activity is not known. In this review a brief summary of the development of FTIs as antitumor agents will be given. The focus of the review will be on important mechanistic and bench-to-bedside translational issues. Among the issues that will be addressed are: evidence for and against inhibition of the prenylation of Ras and RhoB proteins in the mechanism of action of FTIs; implications of the alternative prenylation of K-Ras by geranylgeranyl-transferase I (when FTase is inhibited) in cancer therapy; GGTase I inhibitors (GGTIs) as antitumor agents; effects of FTIs and GGTIs on cell cycle machinery and progression and potential mechanisms by which FTIs and GGTIs induce apoptosis in human cancer cells. A thorough discussion about bench-to-bedside issues relating to hypothesis-driven clinical trials with proof-of-principle in man will also be included. This section will cover issues relating to whether the biochemical target (FTase) is inhibited and the level of inhibition of FTase required for clinical response; are signaling pathways such as H-Ras/PI3K/Akt and/or K-Ras/Raf/MEK/Erk relevant biological readouts?; is Ras (particularly N-Ras and H-Ras) mutation status a good predictor of clinical response?; in phase I trials should effective biological dose, not maximally tolerated dose, be used to determine phase II dose?; and finally, in phase II/III trials what are the most appropriate clinical end points for anti-signaling molecules such as FTIs? Parts of this topic have been recently reviewed (Sebti and Hamilton, 2000c).
1990年，在发现低分子量GTP酶Ras是人类癌症的主要促成因素10多年后，法尼基化（一种Ras致癌活性所需的脂质翻译后修饰）成为新型抗癌药物开发的主要靶点。然而，从1993年首次报道法尼基转移酶抑制剂（FTIs）到1998年描述首个I期临床试验结果，只用了5年时间。这一快速进展归因于FTIs在临床前模型中显示出的出色抗肿瘤活性和无毒性。尽管目前许多FTIs处于II期，至少有一种处于III期临床试验，但FTIs抗肿瘤活性的机制尚不清楚。在本综述中，将简要总结FTIs作为抗肿瘤药物的发展情况。综述的重点将是重要的机制和从 bench 到 bedside 的转化问题。将探讨的问题包括：支持和反对在FTIs作用机制中抑制Ras和RhoB蛋白异戊二烯化的证据；当法尼基转移酶（FTase）被抑制时，香叶基香叶基转移酶I对K-Ras的替代异戊二烯化在癌症治疗中的意义；香叶基香叶基转移酶I抑制剂（GGTIs）作为抗肿瘤药物；FTIs和GGTIs对细胞周期机制和进程的影响以及FTIs和GGTIs诱导人类癌细胞凋亡的潜在机制。还将全面讨论与在人体中进行的具有原理验证的假设驱动临床试验相关的从 bench 到 bedside 的问题。本节将涵盖以下问题：生化靶点（FTase）是否被抑制以及临床反应所需的FTase抑制水平；诸如H-Ras/PI3K/Akt和/或K-Ras/Raf/MEK/Erk等信号通路是否是相关的生物学读数；Ras（特别是N-Ras和H-Ras）突变状态是否是临床反应的良好预测指标；在I期试验中，确定II期剂量时应使用有效生物学剂量而非最大耐受剂量吗；最后，在II/III期试验中，对于诸如FTIs等抗信号分子，最合适的临床终点是什么。本主题的部分内容最近已有综述（Sebti和Hamilton，2000c）。
