IONIZING-RADIATION INHIBITS CHEMOTHERAPY-INDUCED APOPTOSIS IN CULTURED GLIOMA-CELLS - IMPLICATIONS FOR COMBINED-MODALITY THERAPY

Surgical resection followed by radiation therapy is the mainstay of tr eatment for glioblastoma multiforme (GBM), the most aggressive of the malignant gliomas, The poor clinical response of GEM and the intrinsic radiation resistance of this tumor type have prompted clinical invest igations seeking to define the role of chemotherapy in the treatment o f GEM. In this study, we examined the cytotoxic response of GEM-derive d cell lines to treatment with both radiation and chemotherapy. We obs erved that the sensitivity of glioma cells to cisplatin- and FAS-induc ed 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 th e role of p53 in the response of cells to irradiation, we evaluated wh ether p53 function affects the observed radiation-induced resistance t o cisplatin, By examining isogenic cell lines differing only in p53 fu nction, we demonstrated that radiation conferred resistance to cisplat in independently of p53. Current clinical strategies in the treatment of astrocytic tumors, which include combined modality therapy, have be en empirically derived from limited clinical experience. Further under standing of the molecular determinants of apoptosis associated with co mbined modality therapy may guide the design of more efficacious multi modality protocols.