Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development

摘要: Ras proteins are guanine nucleotide-binding that play pivotal roles in the control of normal and transformed cell growth among most intensively studied past decade. After stimulation by various factors cytokines, activates several downstream effectors, including Raf-1/mitogen-activated protein kinase pathway Rac/Rho pathway. In approximately 30% human cancers, a substantial proportion pancreatic colon adenocarcinomas, mutated ras genes produce remain locked an active state, thereby relaying uncontrolled proliferative signals. undergoes posttranslational modifications facilitate its attachment to inner surface plasma membrane. The first-and critical-modification is addition farnesyl isoprenoid moiety reaction catalyzed enzyme farnesyltransferase (FTase). It follows inhibiting FTase would prevent from maturing into biologically form, considerable interest as potential therapeutic target. Different classes inhibitors have been identified block farnesylation Ras, reverse Ras-mediated transformation lines, inhibit tumor cells nude mice. transgenic mice with established tumors, cause regression some which appears be mediated through both apoptosis cycle regulation. well tolerated animal studies do not generalized cytotoxic effects tissues major limitation conventional anticancer agents. There ongoing clinical evaluations determine feasibility administering them on dose schedules like those portend optimal indices preclinical studies. Because unique biologic aspects FTase, designing disease-directed phase II III their effectiveness presents formidable challenges.