Abstract 864 Poster Session II, Sunday, 5/2 (poster 137)

Brain tumors are the most common malignancy of childhood, and these tumors remain a major cause of morbidity and mortality beyond the newborn period. Among childhood brain tumors, astrocytomas occur most frequently and remain among the most resistant to therapy. Following surgery, radiation therapy is a commonly used modality of adjuvant therapy, although astrocytomas are relatively radio-resistant tumors. During the last several years recognition of the role of apoptosis in the response of tumor cells to irradiation and an enhanced understanding of the molecular events by which cells respond to irradiation has provided important radiobiological insights that offer opportunities to pursue more effective treatment strategies for brain tumors.

The radioresistance of astrocytomas is closely associated with the lack of apoptosis which occurs following radiation-induced DNA damage. This characteristic is mimicked in virtually all cell lines derived from such tumors to date. To characterize better inhibition of apoptosis in astrocytoma-derived cell lines, we determined the response of these cells to Fas-mediated cell death. We found that these cell lines, though resistant to radiation-induced apoptosis, readily underwent a P53-independent apoptotic cell death following treatment with anti-Fas antibody. Since radiation-induced apoptosis can be mediated in part through ceramide-induced activation of the Fas pathway, we studied the response of these cell lines to cell permeable ceramide analogues. Treatment of astrocytoma derived cell lines with C2 ceramide induced apoptosis in a dose dependent manner. However, in experiments to date, we have been unable to detect radiation-induced activation of sphingomyelinase or an increase in ceramide production following the irradiation of astrocytoma-derived cell lines. These findings indicate that the inability of astrocytoma-derived cell lines to undergo radiation-induced apoptosis is closely associated with a failure of γ-irradiation to induce ceramide synthesis. These findings suggest that a defect in the cellular pathways responsible for mediating this very early response of cells to irradiation may play an important role in the radiation resistance which characterizes this important childhood tumor.