RAS and leukemia: From basic mechanisms to gene-directed therapy

Purpose and Design: The purpose of this review is to provide an overview of the literature linking Ras signaling pathways and leukemia and to discuss the biologic and potential therapeutic implications of these observations. A search of MEDLINE from 1966 to October 1998 wets performed. Results: A wealth of data has been published on the role of pas pathways in cancer. To be biologically active, pas must move from the cytoplasm to the plasma mem membrane. Importantly, a posttranslational modification-additio n of farnesyl group to the pas C-terminal cysteine-is a requisite for membr ane localization of pas. Farnesylation of pas is catalyzed by an enzyme tha t is designated farnesyltranferase. Recently several compounds have been de veloped that can inhibit farnesylation. preclinical studies indicate that t hese molecules can suppress transformation and tumor growth in vitro and in animal models, with little toxicity to normal cells. Conclusion: An increasing body of data suggests that disruption of pas sign aling pathways, either directly through mutations or indirectly through oth er genetic aberrations, is important in the pathogenesis of a wide variety of cancers. Molecules such as farnesyl transferase inhibitors that interfer e with the function of pas may be exploitable in leukemia (as well as in so lid tumors) as novel antitumor agents. (C) 1999 by American Society of Clin ical Oncology.