Farnesyl
protein transferase inhibitors (FTIs) represent a new class of
anticancer agents specifically targeting aberrant
biologic processes involved with cellular transformation and
malignancy. Originally developed to inhibit
tumors by preventing activation of oncogenic ras genes via suppression of their posttranslational farnesylation, their anticancer activity appears to stem from their ability to inhibit farnesylation of various
proteins that mediate signal transduction, growth, apoptosis, and angiogenesis. The safety,
biologic activity, clinical response, and pharmacokinetics of
R115777, a potent, orally active FTI, were recently investigated in a phase I dose-ranging study in patients with acute
leukemias. Patients with
acute myelogenous leukemia (AML),
acute lymphocytic leukemia (ALL), or
chronic myelogenous leukemia (CML) in
blast crisis received
R115777 100 mg, 300 mg, 600 mg, 900 mg, or 1,200 mg twice daily for 21 days. Cycles were repeated every 28 to 31 days for up to four cycles. An overall response rate of 29% (10/34 evaluable patients) was observed across all
R115777 doses.
R115777 was well tolerated; common adverse events included
fatigue, increased
creatinine,
nausea, and
neutropenia. Dose-limiting toxicity occurred at 1,200 mg twice daily. Farnesylation of
lamin A and HDJ-2, examined as
biologic end points, was inhibited by
R115777 doses > or = 600 mg twice daily. Pharmacokinetic evaluation suggests that
R115777 is concentrated in bone marrow at steady state. The
biologic and antitumor activity and favorable tolerability of
R115777 support further clinical evaluation alone and in combination
therapy in
hematologic malignancies.