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Blood, 1 April 2001, Vol. 97, No. 7, pp. 2008-2015
HEMATOPOIESIS
Comparison of effects of the tyrosine kinase inhibitors AG957,
AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy
between AG490 and STI571
Xuemei Sun,
Judith E. Layton,
Andrew Elefanty, and
Graham J. Lieschke
From the Cytokine Biology Laboratory, Ludwig Institute
for Cancer Research, Melbourne Tumor Biology Branch, The Royal
Melbourne Hospital, Victoria, Australia; and the Walter and Eliza Hall
Institute of Medical Research, The Royal Melbourne Hospital, Parkville,
Victoria, Australia.
STI571 (formerly CGP57148) and AG957 are small molecule inhibitors
of the protein tyrosine kinase (PTK) p145abl
and its oncogenic derivative p210bcr-abl. AG490
is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison
of these inhibitors has previously been reported, so this study
compared their effects on factor-dependent FDC-P1, 32D, and
MO7e cells and their p210bcr-abl-expressing
factor-independent derivatives. STI571 was a more potent inhibitor of
3H-thymidine incorporation in
p210bcr-abl-expressing cells than was AG957,
and it showed superior discrimination between inhibitory effects on
parental cell lines and effects on their
p210bcr-abl-expressing derivatives. Assays
performed with and without growth factor demonstrated that STI571 but
not AG957 reversed the
p210bcr-abl-driven factor
independence of cell lines.
p210bcr-abl-expressing cells were less
sensitive to AG490 than to AG957 or STI571. However, for
p210bcr-abl-expressing clones from all 3 cell
lines, synergistic inhibition was demonstrated between STI571 and
concentrations of AG490 with no independent inhibitory effect.
Inhibition of nucleic acid synthesis with AG957 treatment was
associated with reduced cell numbers, reduced viability, and small
pyknotic apoptotic cells. At concentrations of STI571 that reversed the
p210bcr-abl factor-independent
phenotype, STI571 treatment and growth factor deprivation together were
sufficient to induce apoptosis. This study concludes that, for the
cell lines studied, (1) STI571 is a more potent and more
selective inhibitor of a
p210bcr-abl-dependent phenotype than
AG957; (2) AG490 synergizes with STI571 to enhance its inhibitory
effect on p210bcr-abl-driven proliferation; and
(3) the combination of p210bcr-abl-tyrosine
kinase inhibition and growth factor signal withdrawal can be sufficient
to induce apoptotic death of transformed cells.
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