Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts

Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacc eptable toxicity. Our experimental approach aims to potentiate the therapeu tic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoiso merase I inhibitors are a unique class of chemotherapeutic agents that inte rfere with DNA breakage-reunion by inhibiting the action of topoisomerase I . Preclinical studies suggest that prolonged infusion of topoisomerase I in hibitors enhances fell toxicity due to ionizing radiation, We evaluated the efficacy of combined treatment with continuous administration of topotecan and Y-90-MX-DPTA BrE3 monoclonal antibody (which recognizes an epitope of breast epithelial mucin expressed in most breast cancers) on human mammary carcinoma xenografts in nude mice. Topotecan or Y-90-BrE3 treatment alone d elayed overall tumor growth rate transiently but did not affect survival, T he combination of RIT with topotecan substantially reduced growth of relati vely large established tumors and caused complete tumor regressions and pro longed tumor-free survival in a substantial proportion of treated animals, in vitro studies demonstrated an increase in apoptotic rate and a decrease in cell proliferation of tumor cell lines treated with this combination, We combined the radiosensitization property of topotecan and the specificity of systemic RIT to establish a novel therapy for solid tumors in an experim ental tumor xenograft model.