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 macrophage-derived 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 10(4) C3-L5 cells (and showing lung micrometastases 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 10(4) 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-1 lymphoma targets) lymphocytes with AGM-1+, Lyt-2- and Thy-1 +/- 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 tumor take in this moderately immunogenic tumor model.
Department of Anatomy, University of Western Ontario, London, Canada.
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Lala
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Parhar
D000230:Adenocarcinoma / Q000276:immunology / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D000818:Animals; D004334:Drug Administration Schedule; D005260:Female; D007111:Immunity, Cellular; D007213:Indomethacin / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
D007376:Interleukin-2; D007213:Indomethacin