Potentiation of radioimmunotherapy by inhibition of topoisomerase I.

Cancer therapy with radiolabeled antibodies is limited by the low uptake of radioimmunoconjugates into tumor masses. In this study, camptothecin, a topoisomerase I poison, was examined in vitro and in vivo for potentiation of radioimmunoconjugate therapy. gamma-Ray irradiation of AS-30D rat hepatoma cells followed by a 2-h exposure to camptothecin was found to act additively at low radiation doses (< 200 rad) and synergistically at higher radiation doses as shown by isobologram analysis with 20% survival used as the end point. A monoclonal antibody, RH1, was developed against AS-30D cells and shown to localize in hepatoma ascites in SD rats. Therapy of established ascites tumors with four weekly rounds of either camptothecin administered i.m. in a slow release form or 131I-labeled monoclonal antibody RH1 administered by i.p. injections prolonged rat survival but was ineffective at curing animals of tumors. In contrast, four weekly rounds of combined therapy consisting of i.m. injections of 5 mg/kg camptothecin suspended in lipiodol followed 24 h later by i.p. injection of 200 microCi 131I-labeled monoclonal antibody RH1 cured 86% of animals. Treatment with camptothecin and a 131I-labeled control antibody was no more effective than treatment with drug alone. These results show that camptothecin can potentiate the effects of radiation both in vitro and in vivo and suggest that topoisomerase I inhibitors may be useful for increasing the efficacy of radioimmunoconjugates for the treatment of cancer.