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.