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Department of Anatomy, The University of Western Ontario, London, Ontario, Canada N6A 5C1
We had earlier shown that a single round of interleukin 2 (IL-2) in chronically indomethacin treated mice can totally or nearly totally ameliorate established, experimental lung metastases and reactivate natural killer (NK) and lymphokine activated killer-like cells in the spleen. The present study examined whether a lasting cure of metastasis is obtainable by chronic indomethacin therapy (CIT) combined with single or multiple rounds of IL-2, and if so, what are the morphological, phenotypic, and functional properties of tumoricidal cells generated in situ. Experimental lung metastasis was produced in B6 mice by an i.v. injection of 106 B16F10 melanoma cells to compare therapeutic effects of six protocols: (a) CIT (14 µg/ml via drinking water) starting on day 5 when pulmonary micrometastases are well established; (b) CIT combined with a single round of IL-2 (25,000 units, i.p., every 8 h for 5 days on days 10 through 14); (c) CIT combined with two rounds of IL-2 (days 10–14 and 20–24); (d) two rounds of IL-2 alone; (e) two rounds of IL-2 plus indomethacin given only during the IL-2 therapy; and (f) which was similar to (c), but in addition, followed by repeated injections of IL-2 (25,000 units twice a day on Mondays and Fridays for 8 consecutive weeks). Results revealed that chronic indomethacin therapy alone or two rounds of IL-2 alone, or two rounds of IL-2 plus discontinuous indomethacin therapy reduced the lung metastases (examined at 21–25 days) by about two-thirds. In contrast, both single and multiple rounds of IL-2 in chronically indomethacin treated mice totally or nearly totally eradicated the lung metastases. However, long-term disease-free survival (>13–16 months) resulted only with multiple rounds of IL-2. With chronic indomethacin therapy alone, NK-like (AGM-1+, Thy-1-, Lyt-2-) killer lymphocytes (capable of killing NK sensitive YAC-1 lymphoma and B16F10 melanoma targets) appeared in the spleen, but not lungs; no killer activity was generated in macrophages at either site. Addition of a single round of IL-2 generated lymphokine activated killer-like killer lymphocytes (also capable of killing an NK resistant target) of the same phenotype, but of higher activity in the spleen; some lymphokine activated killer-like killer function was generated among pulmonary lymphocytes which were AGM-1+ Thy-1+, Lyt-2-, as well as among splenic but not pulmonary macrophages. A repetition of IL-2 therapy in these indomethacin treated animals generated the highest tumoricidal activity for all the targets in splenic and pulmonary lymphocytes which expressed AGM-1 as well as Thy-1 but not Lyt-2. Furthermore, significant killer function was now seen among splenic as well as pulmonary macrophages. Injection of AGM-1 antibody into these mice totally annulled the therapeutic effects on lung metastasis as well as killer cell reactivation. These results reveal that chronic indomethacin therapy combined with multiple rounds of IL-2 activates killer cells of the broadest spectrum and geographic distribution including the tumor site to result in a lasting cure of experimental metastasis, AGM-1 bearing cells playing a central role in this cure.
1 Supported by the National Cancer Institute of Canada and the Medical Research Council of Canada.
2 To whom requests for reprints should be addressed.
Received 8/12/87. Revised 11/16/87. Accepted 12/ 3/87.
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