Blood, 1 March 2001, Vol. 97, No. 5, pp. 1399-1403
NEOPLASIA
Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in
P190 transgenic mice with the farnesyl transferase inhibitor
SCH66336
Anja Reichert,
Nora Heisterkamp,
George Q. Daley, and
John Groffen
From the Division of Hematology/Oncology, Ms
#54, Section of Molecular Carcinogenesis, Childrens Hospital of
Los Angeles Research Institute, Los Angeles, CA; and the Division of
Hematology/Oncology, Massachusetts General Hospital, Boston, MA.
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.
