FTIs represent a novel class of anticancer agents that target the signal transduction cascade by preventing the activation ofmutated Ras proteins. The prospect of developing such target-specific agents on the basis of understanding the primary molecular defects that underlie the malignant transformation process presents the intriguing possibility of enhancing antitumor efficacy while sparing normal tissue toxicity. However, despite encouraging results from preclinical studies, it is still unclear as to whether FTIs as a class of agents can inhibit tumor growth in patients with advanced disease, and many challenges exist in their clinical development. An ongoing concern in the development of FTIs relates to the possibility that K-ras inhibition can be circumvented by the occurrence of cross-prenylation by GGTase I. Given, however, the number of physiologic proteins that are known to be substrates for GGTase I, the development of any inhibitors would have be highly selective in nature. Selective inhibitors of GGTase I, including GGTI-2154 and GGTI-298 (68), have in fact been synthesized, and it may be possible to combine these agents with FTIs or cytotoxic agents, to effectively target cells harboring K-ras mutations (68).
There are many unresolved questions pertaining to the development ofFTIs; however, some of the most clinically pointed ones pertain to optimal schedules of administration, selection ofbiologically relevant doses, appropriate endpoints for evaluation in disease-directed studies, which combinations of cytotoxic therapies to pursue, and whether to restrict initial studies to ras-bearing tumors. Regardless of the obstacles that lie ahead, the accumulated biological data obtained thus far indicate that FTIs possess remarkable potential as components of the therapeutic armamentarium against malignant diseases and, possibly, nonmalignant disorders involving aberrant cellular proliferation.
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