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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 639-645
Inhibition of juvenile myelomonocytic leukemia cell growth in
vitro by farnesyltransferase inhibitors
Peter D. Emanuel,
Richard C. Snyder,
Tonya Wiley,
Balaganesh Gopurala, and
Robert P. Castleberry
From the Departments of Medicine and Pediatrics, Divisions of
Hematology/Oncology, Comprehensive Cancer Center, University of Alabama
at Birmingham, Birmingham, AL.
Juvenile myelomonocytic leukemia (JMML) is an early childhood
disease for which there is no effective therapy. Therapy with 13-cis
retinoic acid or low-dose chemotherapy can induce some responses, but
neither mode is curative. Stem cell transplantation can produce lasting
remissions but is hampered by high rates of relapse. The pathogenesis
of JMML involves deregulated cytokine signal transduction through the
Ras signaling pathway, with resultant selective hypersensitivity of
JMML cells to granulocyte-macrophage colony-stimulating factor
(GM-CSF). A JMML mouse model, achieved through homozygous deletion of
the neurofibromatosis gene, confirmed the involvement of deregulated
Ras in JMML pathogenesis. With this pathogenetic knowledge,
mechanism-based treatments are now being developed and tested. Ras is
critically dependent on a prenylation reaction for its signal
transduction abilities. Farnesyltransferase inhibitors are compounds
that were developed specifically to block the prenylation of Ras. Two
of these compounds, L-739,749 and L-744,832, were tested for their
ability to inhibit spontaneous JMML granulocyte-macrophage colony
growth. Within a dose range of 1 to 10 µmol/L, each
compound demonstrated dose-dependent inhibition of JMML colony growth.
An age-matched patient with a different disease and GM-CSF-stimulated
normal adult marrow cells also demonstrated dose-dependent inhibitory
effects on colony growth, but they were far less sensitive to these
compounds than JMML hematopoietic progenitors. Even if the addition of
L-739,749 were delayed for 5 days, significant inhibitory effects would
still show in JMML cultures. These results demonstrate that a putative
Ras-blocking compound can have significant growth inhibitory effects in
vitro, perhaps indicating a potential treatment for JMML.
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