Anti-angiogenic therapy and radioimmunotherapy in colon cancer xenografts

Angiogenesis is critical to the growth and metastatic process of malignant tumors. An endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), displays anti-angiogenic and anti-tumorigenic effects. The purpose of this investigation was to determine whether exogenously administered 2-ME would enhance the efficacy of radioimmunotherapy (RIT). Experimental RIT with 4.63 MBq of I-131-A7, an IgG1 anti-colorectal monoclonal antibody, was conducted in mice xenografted with LS180 human colon cancer cells. 2-ME suspended in 0.5% carboxymethylcellulose was administered daily at a dose of 75 mg/kg per day. 2-ME administration suppressed tumor growth and improved the efficacy of RIT in comparison to RIT alone. Tumor volumes on day 13, expressed as a ratio relative to the initial volume, were 12.7 +/-2.95 in the nontreated control, 4.73 +/-0.89 with 2-ME, 3.05 +/-0.37 with RIT and 0.97 +/-0.20 with RIT+2-ME. Immunohistochemistry of tumor sections stained with an antibody against factor VIII demonstrated a decrease in microvessel number within tumors treated with 2-ME (7.9 +/-0.8/200x field) as compared with that in control tumors (29.9 +/-2.5). Cell proliferation assay at increasing concentrations of 2-ME showed direct cytotoxicity of 2-ME in vitro at 5 muM and greater. In conclusion, 2-ME enhanced the efficacy of RIT with I-131-A7 via inhibition of angiogenesis within the xenografts. The direct cytotoxicity of 2-ME appears to have contributed to this improvement. Anti-angiogenic therapy may prolong the dormancy of microscopic metastases while RIT may exterminate this population of cells. Therefore. the combined treatment may improve the therapeutic outcome of patients with disseminated cancer.