Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects.
Farnesyltransferase (FTase) inhibitors are among the current wave of molecularly targeted anti-cancer agents being used to attack malignancy in a rational manner. A large body of preclinical data indicates that FTase inhibitors block cancer cell proliferation through both cytostatic and cytotoxic effects. Interestingly, FTase inhibitors have rather limited effects on normal cell function, suggesting that they may target unique aspects of cancer cell pathophysiology. The development of FTase inhibitors was predicated on the discovery that the Ras oncoproteins must be post-translationally modified to transform cells. However, recent work indicates that the anti-neoplastic effects of FTase inhibitors depend on altering the post-translational modifications of non-Ras proteins as well. In particular, a critical target protein that responds to FTase inhibition by blocking tumor cell growth is RhoB, an endosomal Rho protein that functions in receptor trafficking. In this review, we survey the biological foundations for the clinical development of FTase inhibitors, and consider some of the latest mechanistic studies that reveal how these agents affect cellular physiology.
Prendergast
G C
GC
Department of Cancer Research, Dupont Pharmaceuticals Company, Glenolden Laboratory, Glenolden, PA 19036, USA.
Oliff
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D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002448:Cell Adhesion; D002986:Clinical Trials as Topic; D003599:Cytoskeleton; D051231:Farnesyltranstransferase; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; D020743:rhoB GTP-Binding Protein