ADENOVIRUS-MEDIATED P53 GENE DELIVERY POTENTIATES THE RADIATION-INDUCED GROWTH-INHIBITION OF EXPERIMENTAL BRAIN-TUMORS

Patients with malignant gliomas continue to have very poor prognosis e ven after surgical resection, radiation and chemotherapy. Because thes e tumors often have alterations in the p53 tumor suppressor gene, whic h plays a key role in the cellular response to DNA damaging agents, we investigated the role of p53 gene therapy in conjunction with ionizin g radiation in a rat brain tumor model. Exposure of cultured rat 9L gl iosarcoma cells, which contain a mutant p53 gene, to a recombinant ade novirus-vector bearing the wild-type p53 gene (Adp53), induced apoptos is within 24 hours. Although ionizing radiation had no additional effe ct on apoptosis within this time frame, it caused G(1) arrest in non-a poptotic cells after Adp53 therapy. In contrast, wild-type 9L cells de monstrated little G(1) arrest after X-irradiation. When animals bearin g brain tumors were irradiated after intratumoral Adp53 injections, mo re than 85% reduction in tumor size was noted. Moreover, the group of rats receiving both radiation and Adp53 therapy had a significant incr ease in survival as compared to animals receiving either therapy alone . These results support the use of p53 gene therapy as an adjunct to r adiation in treatment of malignant brain tumors.