Synergy between vascular targeting agents and antibody-directed therapy

Purpose: Tumor heterogeneity necessitates the use of combined therapies. We have shown that combining antibody-directed therapy with antivascular agents converts a subcurative to a curative treatment. The purpose of this study was to investigate, by radioluminographic and microscopic techniques, the regional effects of the two complementary therapies. Methods and Materials: Nude mice bearing colorectal tumors were injected with (125)I-labeled anti-carcinoembryonic antigen antibody, and images were obtained for antibody distribution and modeling studies using radioluminography. For therapy studies, the mice were given radioimmunotherapy alone ((131)I-A5B7 anti-carcinoembryonic antigen antibody), the antivascular agent combretastatin A-4 3-0-phosphate (200 mg/kg), or both. Extra mice were used to study the regional tumor effects of these therapies over time: relevant histochemical procedures were performed on tissue sections to obtain composite digital microscopic images of apoptosis, blood vessels, perfusion, hypoxia, and morphology. Results: Antibody distribution, modeling, and immunohistochemistry showed how radioimmunotherapy (7.4 MBq/40 mug antibody) effectively treated the outer, well-oxygenated tumor region only. Combretastatin A-4 3-0-phosphate treated the more hypoxic center, and in doing so altered the relationship between tumor parameters. Conclusion: The combined complementary therapies produced cures by destroying tumor regions with different pathophysiologies. Relating these regional therapeutic effects to the relevant tumor parameters microscopically allows optimization of therapy and improved translation to clinical trials. (C) 2002 Elsevier Science Inc.