Eradication of spontaneous and experimental adenocarcinoma metastases with chronic indomethacin and intermittent IL‐2 therapy

We had earlier shown that tumor‐bearing results in an inactivation of IL‐2–dependent effector cells by host macrophagederived PGE2, and that chronic indomethacin therapy (CIT) aimed at blocking prostaglandin synthesis, combined with multiple rounds of IL‐2, can cure experimental metastases of a variety of tumors in mice. We have now tested the efficacy of this therapy on spontaneous as well as experimental metastasis of C3–L5 mammary adenocarcinoma in C3H/HeJ mice. Mice transplanted s.c. with C3–L5 cells (and showing visible spontaneous lung metastases between days 7 and 10) were given CIT starting on day 15, plus 2 5–day rounds of IL‐2 or IL‐2 alone. Mice injected i.v. with 104 C3–L5 cells (and showing lung micrometas‐tases on day 5) were placed on CIT on day 5 and given 3 5–day rounds of IL‐2 or treated with IL‐2 alone. Control mice received vehicles alone. Results revealed that combined CIT + IL‐2 therapy in the spontaneous metastasis model caused a regression of primary tumors, a marked reduction in lung metastases scored on days 25–35 and a marked prolongation of host survival (79% cured). Survivors rechallenged with 104 tumor cells i.v. on day 210 resisted tumor growth. In the experimental metastasis model, this therapy also markedly reduced lung metastases and prolonged animal survival (50% cured). In both models, the combination therapy led to the presence of highly active tumoricidal (for C3–L5 and YAC‐I lymphoma targets) lymphocytes with AGM‐I+, Lyt‐2‐ and Thy‐l± phenotype and macrophages in the spleen and the lungs, and ADCC‐promoting activity in the serum. CIT + IL‐2 therapy can thus effectively eradicate spontaneous and experimental mammary adenocarcinoma metastasis in mice. It activates natural effector cells in situ, generates ADCC‐promoting activity in the serum and results in resistance to umor take in this moderately immunogenic tumor model.