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.