Evolving therapies: farnesyltransferase inhibitors.
Farnesyltransferase inhibitors (FTIs) are compounds designed to interfere with the signal transduction of cancer cells containing ras gene mutations. Specifically, FTIs were designed to prevent the farnesylation of Ras and other intracellular proteins, and they have been shown to have an effect on malignant cell proliferation and survival. However, the actual intracellular target of FTIs and the cellular determinants of drug action that correlate with antitumor effects currently are unknown. The following are key questions relating to FTI cell biology and clinical development: 1) Are ras gene mutations required for FTIs to be effective? 2) Does the effect of FTI therapy depend on which ras isoform is active (ie, H-ras, K-ras4A/B, or N-ras) in cancer cells? 3) What level of farnesyltransferase inhibition is required for clinical effect? 4) What surrogate biomarkers can be used to evaluate the biologic effect of FTIs in ongoing clinical trials? 5) What is the mechanism of FTI antitumor activity? Although the preliminary results are encouraging, more understanding of the intracellular mechanism of the FTIs is needed to determine how best to administer them in patients with cancer and to test their antitumor effects.
Purcell
W Thomas
WT
The Johns Hopkins Oncology Center, 1650 Orleans Street, Bunting-Blaustein Cancer Research Building, Room 187, Baltimore, MD 21231-2410, USA. rdonehow@jhmi.edu
Donehower
Ross C
RC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051231:Farnesyltranstransferase; D006801:Humans; D008956:Models, Chemical; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D017368:Protein Prenylation / Q000187:drug effects*; D013379:Substrate Specificity; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins