title: Farnesyltransferase inhibitors: novel compounds in development for the treatment of myeloid malignancies.
abstract: The farnesyltransferase inhibitors (FTIs) have been shown in early clinical trials to elicit antitumor actions in a broad range of solid and hematologic malignancies. The mechanism of FTI action involves blockade of farnesyltransferase, an enzyme implicated in multiple cell-signaling pathways involved in proliferation, angiogenesis, or decreased apoptosis. Of the four main classes of FTIs, two orally bioavailable FTIs have advanced farthest in clinical development. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ) and Sarasar (formerly SCH66336, Schering-Plough, Kenilworth, NJ) have demonstrated biologic and clinical activity in a range of solid tumors, and Zarnestra phase I trials have documented clinical responses in approximately 30% of patients with high-risk leukemias or myelodysplastic syndrome (MDS). The main across-class toxicities associated with the use of FTIs are myelosuppression and fatigue. Certain toxicities, such as the QTc abnormalities associated with L-778,123, do not appear to be class related. As results of phase II trials with FTIs in acute and chronic myeloid leukemias and in MDS become available, clinicians will learn more about the potential role of this class of targeted anticancer drugs-and possibly about the clinical distinctions among members of this class.
authors.affiliation: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase