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Radiosensitization of Tumor-targeted Radioimmunotherapy with Prolonged Topotecan Infusion in Human Breast Cancer Xenografts¹

Laboratory of Cell Biology, Biology Department, New York University, New York, New York 10003 (B. N., P. F.); Divisions of Nuclear Medicine (E. K.) and Oncology (L. L., C. W., H. H.), New York University Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016 (E. K., L. L., C. W., H. H., P. F.); and Cancer Research Fund of Contra Costa, Walnut Creek, California 94596 (E. B., R. C.)

Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacceptable toxicity. Our experimental approach aims to potentiate the therapeutic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoisomerase I inhibitors are a unique class of chemotherapeutic agents that interfere with DNA breakage-reunion by inhibiting the action of topoisomerase I. Preclinical studies suggest that prolonged infusion of topoisomerase I inhibitors enhances cell toxicity due to ionizing radiation. We evaluated the efficacy of combined treatment with continuous administration of topotecan and ⁹⁰Y-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 ⁹⁰Y-BrE3 treatment alone delayed overall tumor growth rate transiently but did not affect survival. The combination of RIT with topotecan substantially reduced growth of relatively large established tumors and caused complete tumor regressions and prolonged 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 experimental tumor xenograft model.

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