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Ionizing Radiation Inhibits Chemotherapy-induced Apoptosis in Cultured Glioma Cells: Implications for Combined Modality Therapy¹

Preuss Laboratory for Molecular Neuro-oncology, Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143

Surgical resection followed by radiation therapy is the mainstay of treatment for glioblastoma multiforme (GBM), the most aggressive of the malignant gliomas. The poor clinical response of GBM and the intrinsic radiation resistance of this tumor type have prompted clinical investigations seeking to define the role of chemotherapy in the treatment of GBM. In this study, we examined the cytotoxic response of GBM-derived cell lines to treatment with both radiation and chemotherapy. We observed that the sensitivity of glioma cells to cisplatinand FAS-induced apoptosis was diminished by prior treatment with ionizing radiation. Radiation conferred resistance to cisplatin and FAS cytotoxicity in a dose- and time-dependent manner. Radiation diminished the cisplatin-induced cytotoxicity of malignant glioma cells but failed to alter the cisplatin susceptibility of normal primary human astrocytes. Given the role of p53 in the response of cells to irradiation, we evaluated whether p53 function affects the observed radiation-induced resistance to cisplatin. By examining isogenic cell lines differing only in p53 function, we demonstrated that radiation conferred resistance to cisplatin independently of p53. Current clinical strategies in the treatment of astrocytic tumors, which include combined modality therapy, have been empirically derived from limited clinical experience. Further understanding of the molecular determinants of apoptosis associated with combined modality therapy may guide the design of more efficacious multimodality protocols.

¹ Supported in part by NIH Grants CA 13525 (to M. A. I.) and M01RR01271 (to D. A. H-K.) and awards from the Betz Foundation (to M. A. I.) and Radiological Society of North America (D. A. H-K.). G. L. Y. is a recipient of the Robert Steel Foundation for Pediatric Cancer Research Fellowship.

² Present address: Department of Radiation Oncology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0226.

³ Present address: Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0506.

⁴ To whom requests for reprints should be addressed, at Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, Health Sciences East 722, 513 Parnassus Avenue, San Francisco, CA 94143-0520. Phone: (415) 476-6662; Fax: (415) 476-0388; E-mail: israel@cgl.ucsf.edu.

Received 3/ 6/98. Accepted 7/ 1/98.

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