The Philadelphia (Ph) chromosome is found in approximately 3% of pediatric patients with
acute lymphoblastic leukemia (ALL) and the percentage markedly increases in adult patients. The prognosis for this class of patients is poor, and no standard
chemotherapy combination so far has demonstrated long-term efficacy. The Ph-translocation joins the BCR and ABL genes and leads to expression of a chimeric Bcr/Abl
protein with enhanced
tyrosine kinase activity. This increase in activity leads to malignant transformation by interference with basic cellular functions such as the control of proliferation, adherence to stroma and extracellular matrix, and apoptosis. One important pathway activated by Bcr/Abl is the Ras pathway.
Ras proteins have to undergo a series of posttranslational modifications to become biologically active. The first modification is the farnesylation of the C-terminus catalyzed by farnesyl
transferase. We studied the effect of the farnesyl
transferase inhibitor
SCH66336 in an in vivo murine model of Bcr/Abl-positive
acute lymphoblastic leukemia. In the early leukemic phase, mice were randomly assigned to a treatment, a vehicle, and a nontreatment group. The treatment was well tolerated without any detectable side effects. All animals of the control groups died of
leukemia/
lymphoma within 103 days (range, 18-103 days). In contrast, 80% of the
drug-receiving group survived without any signs of
leukemia or
lymphoma until termination of treatment, after a median treatment period of 200 days (range, 179-232 days). We conclude that farnesyl
transferase inhibitor
SCH66336 is able to revert early signs of
leukemia and significantly prolongs survival in a murine ALL model.