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New Agent May Help Overcome Imatinib Resistance

New Agent May Help Overcome Imatinib Resistance

SAN FRANCISCO—In vitro studies suggest that a new anticancer agent,
SCH66336, can slow cell proliferation in drug-resistant forms of Philadelphia
(Ph)-positive leukemia, according to a presentation by Japanese researchers at
the 93rd Annual Meeting of the American Association for Cancer Research
(abstract 4235). When used in combination with antileukemic agents, SCH66336
induced apoptosis in leukemia cells resistant to imatinib mesylate (Gleevec).

"SCH66336 is a promising candidate for treating patients with Gleevec-resistant
Ph-positive leukemias," said Tetsuzo Tauchi, MD, PhD, associate professor
of internal medicine, Tokyo Medical University. "Gleevec has shown promise
in human clinical trials of Ph-positive leukemia, but the emergence of drug
resistance in patients with acute forms of Ph-positive leukemia highlights the
need for combination chemotherapy to eradicate the disease."

In the cell line study, SCH66336 and/or imatinib was added to
BCR-ABL-positive acute myelogenous leukemia (AML) cells in culture. BCR-ABL is
a chimeric oncoprotein generated by the Philadelphia chromosome in Ph-positive
leukemia. Imatinib inhibits the tyrosine kinase activity of BCR-ABL in leukemia

The scientists counted cell numbers every 24 hours for 5 days. When the
cells were treated with SCH66336, cell growth was inhibited more than when they
were treated with imatinib alone. In contrast to cells treated with imatinib,
those treated with SCH66336 showed significant antiproliferative effects.

Despite the inhibition of cell proliferation, SCH66336-treated cells
remained viable after 1 week in culture. Yet treatment with imatinib and
SCH66336 together significantly increased apoptosis, compared with imatinib or
SCH66336 alone.

The scientists also investigated whether SCH66336 could increase the effects
of some antileukemic agents, including imatinib, in chronic myelogenous
leukemia (CML) blast crisis cell lines. When SCH66336 was used with imatinib or
cytosine arabinoside (ara-C), the antiproliferative activity of the drug
combination increased. However, when the new compound was combined with
daunorubicin (Cerubidine) or etoposide (VePesid), there was no increased
antiproliferative effect.

The researchers then tested how leukemic bone marrow cells would react to
the combination of SCH66336 and imatinib mesylate. The results showed that the
combination produced a substantial decrease in colony formation, compared with
that seen with each agent alone.


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