R115777 is a nonpeptidomimetic enzymespecific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (acti- vated
IntroductionAdult acute leukemias remain formidable therapeutic challenge. Only 70% of adults with newly diagnosed acute myelogenous leukemias (AMLs) achieve complete remission (CR) after cytotoxic induction chemotherapy. Although these CRs may be prolonged in 35% to 40% of younger adults (age Ͻ 60), 1-5 the remainder have a relapse and die. Certain subgroups, including older adults, 3,5,6 patients with AMLs linked to environmental or occupational exposures (including therapy-induced AMLs), and patients with previous myelodysplasia (MDS) or other antecedent hematologic disorders, 7,8 have extremely poor outcomes, with CR rates of 40% or less, CR durations less than 12 months, and cure rates less than 10% to 15%. 3,5,6 The overall outlook for adult acute lymphoblastic leukemias (ALLs) is similar, 9-11 with a particularly poor prognosis in Philadelphia chromosome (Ph ϩ ) disease. 9,12 Thus, new approaches are needed to improve the outcome for adults with refractory leukemias.Improved understanding of signal transduction pathways has resulted in identification of a panoply of potential therapeutic targets. [13][14][15][16] Among these are the membrane-associated G proteins encoded by the ras family of proto-oncogenes. Ras proteins are activated downstream of protein tyrosine kinases (PTKs, eg, growth factor receptors) and, in turn, trigger a cascade of phosphorylation events through sequential activation of Raf, MEK-1, and ERKs (extracellular signal-related kinases). These events are critical to survival of hematopoietic cells. [16][17][18][19] The Ras proteins are synthesized as cytosolic precursors that must attach to the cell membrane to transmit signals. Membrane attachment depends on the addition of a 15-carbon farnesyl group to Ras, a reaction that is catalyzed by the enzyme farnesyltransferase (FT). [20][21][22] FT inhibitors (FTIs) were developed on the premise that FT inhibition would prevent Ras processing and, therefore, transduction of proliferative signals. [22][23][24] Subsequent studies, however, have suggested that the cytotoxic actions of FTIs might also involve other farnesylated ...
