Effect of indomethacin on tumorigenicity and immunity induction in a murine model of mammary carcinoma.

Indomethacin, an inhibitor of cyclo-oxygenase given orally, reduced the tumorigenicity of cancer cells in a non-immunogenic murine model of mammary adenocarcinoma (4T1). In the presence of indomethacin, a dose-dependent immune protection could be induced most effectively by immunizing mice with 1 to 3 doses of irradiated tumor cells inoculated at intervals of 7 days prior to challenge with a tumorigenic cell dose. Three immunizations given without indomethacin resulted in tumor growth in 88% of the recipients, and indomethacin treatment started 28 days prior to the challenge dose and given without immunizations led to tumor onset in 83% of mice. In contrast, tumor was documented only in 12% of mice vaccinated with 3 immunization doses and given concomitantly indomethacin. Moreover, 53% of disease-free survivors resisted a second challenge with a high tumorigenic dose. Induction of an anti-tumor immunity in indomethacin-treated mice was further studied as a therapy for tumor-bearing mice. Complete cure was induced in 50% of mice, and a significant reduction in tumor size as well as prolonged survival time were observed in the remaining animals. Immunostimulation by tumor cell vaccination given in the presence of a tolerable dose of indomethacin, therefore, may be incorporated into immunotherapy protocols to activate an anti-tumor response against residual tumor cells that escaped surgery and/or high-dose chemo/radiotherapy.