IRINOTECAN AND RADIATION IN-VITRO AND IN-VIVO

Topoisomerase I inhibitors have shown positive effects in combination with radiation therapy in some studies. Normally oxygenated and hypoxi c human MCF-7 breast carcinoma-cells were exposed to irinotecan (100 m u M or 250 mu M) or to SN-38 (10 mu M or 25 mu M) for 1 h prior to, du ring and for 3 h after radiation. Irinotecan and SN-38 showed little o r no radiation sensitization of normally oxygenated MCF-7 cells but we re effective radiation sensitizers of hypoxic cells. Both irinotecan a nd SN-38 diminished or eliminated the shoulder of the radiation surviv al curves of both the normally oxygenated and hypoxic cells indicating inhibition of the repair of sublethal radiation damage to DNA. Irinot ecan (20 mg/kg or 30 mg/kg) was administered to mice bearing the EMT-6 mammary carcinoma on days 7 through 11 just prior to fractionated rad iation (5x3 Gray). The tumor growth delays obtained with the combinati on regimens were greater than expected for simple additivity of the tw o treatments. Treatment with irinotecan resulted in decreased expressi on of topoisomerase I mRNA and increased expression of topoisomerase I I mRNA in EMT-6 tumor tissue. Irinotecan treatment did not alter the p rotein levels for topoisomerase I or II in the tumor tissue; however, the combination of radiation therapy and irinotecan administration res ulted in decreased topisomerase I and increased topoisomerase II prote in in the tumor tissue. These results suggest that with appropriate sc heduling of a topoisomerase I inhibitor and a topoisomerase II inhibit or with fractionated radiation therapy maximal cyto-reduction can be a chieved.