Therapeutic efficacy on c-kit and PDGF receptor tyrosine kinase inhibitor STI-571 on gliomas and metastatic brain tumors

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STI 571 known as a tyrosine kinase inhibitor for bcr-abl, PDGF receptor and c-kit exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors. The present study focuses on the anti-cancer activity of STI 571 in glioma cells in vitro and in vivo. Growth inhibitory effects of STI 571 on several glioma cell lines (SRB10A, RT2, C6, 9L, U87MG, T98G), PC-3 prostate cancer cells, B16 melanoma cells, primary tumor cells in patients with glioblastoma and metastatic brain tumor surgically obtained were assessed by MTT assay and cytotoxic assay. STI 571 inhibits tumor cell proliferation and growth in vitro. IC50 of STI 571 on these cells were between 10 μ M and 15μ M, although that of KU812 chronic myeloid leukemia cells was 40 nM. STI 571 inhibits the growth of subcutaneous SRB10A mouse glioma and B16 melanoma, but it did not inhibit intracranial growth of B16. In addition, combination therapy with STI 571 and TNP 470, an angiogenesis inhibitor enhanced anti-cancer activity in vivo. These results suggest that inhibition of c-kit and PDGF signal pathway plus angiogenesis inhibitor may contribute the enhancement of therapeutic effects of chemotherapy on malignant solid tumors.