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Tumor Biology |
Divisions of Neurology (A.J.J., C.B.T., P.C.P.), Oncology (A.J.J., P.C.P.), and Neurosurgery (L.S.), Children's Hospital of Philadelphia, 324 South 34th St., Philadelphia, PA 19104-9786; and Departments of Radiation Oncology (A.M., W.G.M.) and Pathology and Laboratory Medicine (R.J.M.), University of Pennsylvania School of Medicine, Philadelphia, PA 19104
2 Address correspondence and reprint requests to Anna J. Janss, Division of Neurology, Children's Hospital of Philadelphia, 324 South 34th St., Philadelphia, PA 19104-9786.
Abstract
DNA damage produces delayed mitosis (G2/M delay) in proliferating cells, and shortening the delay sensitizes human malignant glioma and medulloblastoma cells to cytotoxic chemotherapy. Although activation of the cyclin-dependent kinase CDC2 mediates G2/M transition in all tumor cells studied to date, regulation of CDC2 varies between tumor types. Persistent hyperphosphorylation of kinase and reduced cyclin expression have been implicated as mediators of treatment-induced G2 delay in different tumor models. To evaluate regulation of G2/M transition in human brain tumors, we studied the expression and/or activity of CDC2 kinase and cyclins A and B1 in U-251 MG and DAOY medulloblastoma cells after their treatment with camptothecin (CPT). Synchronized cells were treated during S phase, then harvested at predetermined intervals for evaluation of cell cycle kinetics, kinase activity mRNA, and protein expression. CPT produced G2 delay associated with decreased CDC2 kinase activity and cyclin B1 expression. Kinase activity was associated with CDC2 bound to cyclin B1, not cyclin A, in both cell lines. Cyclin A mRNA and protein expression were reduced after CPT treatment; however, decreased protein expression was short lived and moderate in the glioma and primitive neuroectodermal tumor/medulloblastoma cells, respectively. We conclude that G2 delay is a common response of brain tumor cells to chemotherapy with topoisomerase I inhibitors and that a mechanism of this delay may be reduced expression of cyclin B1.
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