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Monday 21st February, 2005
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AMN107, is about 20 times more potent than Gleevec and is effective
in treating Gleevec-resistant disease.
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BOSTON--A laboratory study led by researchers at Dana-Farber
Cancer Institute has shown that a potent and highly selective
therapy for chronic myelogenous leukemia (CML) may ultimately be
more effective than Gleevec?, the current standard of care. The
researchers report in the February issue of Cancer Cell that the
new compound, AMN107, is about 20 times more potent than Gleevec
and is effective in treating Gleevec-resistant disease in model
systems. Discovered by and in development with Novartis Pharma
AG, AMN107 is a small molecule tyrosine kinase inhibitor.
"While Gleevec represents a major treatment advance for CML ?
approximately 95 percent of patients treated with Gleevec
achieve remission ? there clearly is a need for therapies that
produce longer remissions, are active against advanced disease,
and can be used when Gleevec loses effectiveness," says
Dana-Farber's James Griffin, MD, senior author of the study.
Gleevec shuts down CML by blocking the function of Bcr-Abl,
the abnormal tyrosine kinase protein in the leukemic cells that
causes them to grow too quickly. However, it does not bind very
tightly to this protein, and patients can develop a resistant
type of Bcr-Abl that no longer binds to Gleevec at all.
Using rational drug design to circumvent these shortcomings,
researchers at Novartis determined the crystal structure of
Bcr-Abl, and then constructed compounds that would lock into the
receptor more securely than Gleevec. Investigators at
Dana-Farber tested the new compounds to measure their
effectiveness against CML in laboratory cell cultures and mice
with the disease.
Data from the study published in Cancer Cell showed that in
experiments with laboratory samples of CML cells, AMN107 killed
the cells more effectively than Gleevec. In follow-up studies
with mice with a human form of CML, AMN107 produced lengthier
remissions than Gleevec and triggered remissions in animals in
which the disease had become resistant to Gleevec. Side effects
in the animals were minimal.
Synthesized in August 2002, AMN107 entered early Phase I
clinical studies in May 2004 ? 21 months later. Data presented
last December at the American Society of Hematology showed that
AMN107 had demonstrated significant clinical activity in the
most challenging setting: Gleevec resistant accelerated and
blast crisis CML patients.
"We're very encouraged by the results so far," remarks
Griffin, who is also a professor of medicine at Harvard Medical
School. "This is an elegant example of how rational drug design
?? developing drugs based on a molecular understanding of cell
structures and processes ?? can be used to attack human
diseases."
The findings contribute to a larger Dana-Farber research
effort, dubbed the "Kinase Project," which seeks to identify
abnormal tyrosine kinases -- enzymes that spark or halt growth
-- in cancer cells and test agents known to act against them.
The Cancer Cell study's lead author is Ellen Weisberg, PhD,
of Dana-Farber. Co-authors include researchers at Dana-Farber,
Novartis, Brigham and Women's Hospital, and Children's Hospital
Boston.
Sources
Dana-Farber Cancer Institute.
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