Journal of Clinical Oncology, Vol 17, Issue 11
(November), 1999: 3631-3652
© 1999 American Society for Clinical Oncology
Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development
Eric K. Rowinsky,
Jolene J. Windle,
Daniel D. Von Hoff
From the Institute for Drug Development, Cancer Therapy and Research Center; and the University of Texas Health Science Center, San Antonio, TX.
Address reprint requests to Eric K. Rowinsky, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 700, San Antonio, TX 78229-3272; email erowinsk{at}saci.org
ABSTRACT
ABSTRACT: 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.
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