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Intracranial
inhibition of platelet-derived growth factor-mediated glioblastoma cell growth
by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class
Kilic T, Alberta JA, Zdunek PR, Acar M, Iannarelli P, O'Reilly T, Buchdunger
E, Black PM, Stiles CD
Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women's Hospital,
and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115,
USA
Glioblastoma multiforme is the most common primary human brain tumor, and it is,
for all practical purposes, incurable in adult patients.
The high mortality
rates reflect the fact that glioblastomas are resistant to adjuvant therapies
(radiation and chemicals), the mode of action of which is cytotoxic.
We show
here that an p.o.-active small molecule kinase inhibitor of the
2-phenylaminopyrimidine class may have therapeutic potential for glioblastomas.
STI571 inhibits the growth of U343 and U87 human glioblastoma cells that have
been injected into the brains of nude mice, but it does not inhibit intracranial
growth of ras-transformed cells.
Studies on a broad panel of genetically
validated human and animal cell lines show that STI571 acts by disruption of the
ligand:receptor autocrine loops for platelet-derived growth factor that are a
pervasive feature of malignant astrocytoma.
The cellular response of
glioblastoma cells to STI571 does not appear to involve an apoptotic mechanism.
PMID:
11016641 [PubMed - indexed for MEDLINE]
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