Inhibition of Tumor Growth in Association with Modification of in Vivo Immune Response by Indomethacin and Polyinosinic:Polycytidylic Acid¹

Inhibition of tumor growth in a murine transplantable model of bladder cancer was attempted through manipulation of immune response mechanisms by treatment of experimental animals with indomethacin, a prostaglandin synthetase inhibitor, and/or polyinosinic:polycytidylic acid [poly(I:C)], an inducer of interferon. Tumor-bearing animals and age-matched controls were inoculated i.p. with either phosphate-buffered saline or 200 to 400 µg indomethacin, and/or 10 µg poly(I:C) on alternate days for 3 to 5 total doses. At selected intervals, splenic lymphocytes were prepared for cytotoxicity testing against ⁵¹Cr-labeled target cell lines. The greatest degree of inhibition was seen when both poly(I:C) and indomethacin were inoculated into experimental animals. Poly(I:C) alone also inhibited tumor growth, but to a lesser degree. Indomethacin was the least effective in inhibiting tumor growth. Splenic lymphocytes from both tumor-bearing and control animals that had been inoculated with poly(I:C) demonstrated the highest levels of cytotoxicity, while comparable animals treated with indomethacin alone showed no alteration of cytotoxicity levels in comparison with animals treated with only phosphate-buffered saline. Although tumor growth had been inhibited to the greatest extent with combined poly(I:C)-indomethacin treatment, lymphocyte cytotoxicity in these animals was less than that seen in animals treated with poly(I:C) alone. Addition of interferon directly to the cytotoxicity assay further enhanced lymphocyte cytotoxicity in lymphocytes derived from all animals except those treated with poly(I:C) alone. In vitro addition of indomethacin did not change cytotoxicity levels seen in any experimental group. Taken together, interferon induction and prostaglandin synthetase inhibition appeared to exert the greatest effect in controlling tumor growth. Corresponding effects on cytotoxicity did not confirm that the effect of these agents in vivo on tumor growth reflected an effect on the immune response. Further studies are needed to confirm the hypothetical cause-effect relationship in this experimental model.