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 131I-A7, an
IgG1 anti-colorectal
monoclonal antibody, was conducted in mice xenografted with LS 180 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 microM and greater. In conclusion,
2-ME enhanced the efficacy of RIT with 131I-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.