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[Cancer Research 60, 5143-5150, September 15, 2000]
© 2000 American Association for Cancer Research

Experimental Therapeutics

Intracranial Inhibition of Platelet-derived Growth Factor-mediated Glioblastoma Cell Growth by an Orally Active Kinase Inhibitor of the 2-Phenylaminopyrimidine Class1

Turker Kilic2,3, John A. Alberta2, Pawel R. Zdunek4, Melih Acar5, Palma Iannarelli, Terence O’Reilly, Elisabeth Buchdunger, Peter M. Black and Charles D. Stiles6

Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women’s Hospital, The Children’s Hospital, and Department of Surgery, Harvard Medical School [T. K., P. R. Z., M. A., P. M. B.], and Department of Microbiology and Molecular Genetics, Harvard Medical School and the Dana-Farber Cancer Institute [J. A. A., P. I., C. D. S.], Boston, Massachusetts 02115, and Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland [T. O., E. B.]

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.




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