Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336

The Philadelphia (Ph) chromosome is found in approximately 3% of pediatric patients with acute lymphoblastic leukemia (ALL) and the percentage markedl y 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 a ctivity. This increase in activity leads to malignant transformation by int erference with basic cellular functions such as the control of proliferatio n, adherence to stroma and extracellular matrix, and apoptosis. One importa nt pathway activated by Bcr/Abl is the Ras pathway. Ras proteins have to un dergo a series of posttranslational modifications to become biologically ac tive. The first modification is the farnesylation of the C-terminus catalyz ed by farnesyl transferase. We studied the effect of the farnesyl transfera se inhibitor SCH66336 in an in vivo murine model of Bcr/Abl-positive acute lymphoblastic leukemia. In the early leukemic phase, mice were randomly ass igned to a treatment, a vehicle, and a nontreatment group. The treatment wa s well tolerated without any detectable side effects. All animals of the co ntrol groups died of leukemia/lymphoma within 103 days (range, 18-103 days) . In contrast, 80% of the drug-receiving group survived without any signs o f leukemia or lymphoma until termination of treatment, after a median treat ment period of 200 days (range, 179-232 days). We conclude that farnesyl tr ansferase inhibitor SCH66336 is able to revert early signs of leukemia and significantly prolongs survival in a murine ALL model. (Blood, 2001;97:1399 -1403) (C) 2001 by The American Society of Hematology.