Potentiation of nonspecific immunotherapy of experimental lung metastases by indomethacin.
Intraperitoneal treatment with the interferon inducer, maleic anhydride-divinyl ether copolymer (MVE), has previously been demonstrated to effectively reduce metastatic growth in the lungs and prolong survival times of BALB/c mice bearing the syngeneic Madison lung (M109) carcinoma. Resistance to lung metastasis formation induced by MVE appears to result from an activation of alveolar macrophage function. Since E-type prostaglandins (PGE) suppress the cytotoxic activity of activated macrophages, we sought to determine the effect of indomethacin, a prostaglandin synthetase inhibitor, on the antimetastatic activity of MVE. An artificial metastasis model was developed in which single-cell suspensions of the M109 tumor were injected i.v. into BALB/c mice. A 52,600 molecular weight fraction of MVE (MVE-5) was administered i.p. at 20 mg/kg two days prior to tumor inoculation. MVE-5 treatment produced greater than 80 percent reduction in macroscopic lung lesion formation at Day 15 and Day 19 after tumor inoculation and a resultant 45 percent increase in lifespan. Chronic administration of indomethacin in the drinking water at 10 micrograms/ml potentiated the MVE-5 antitumor induced macrophage activation in vivo. In the absence of any evidence for an interaction between indomethacin and circulating M109 cells, it was felt that the potentiating effect could be best explained in terms of interference with PGE-mediated feedback inhibition of macrophage functional activity.
D000818:Animals; D002277:Carcinoma / Q000556:secondary* / Q000628:therapy; D016861:Cyclooxygenase Inhibitors; D004357:Drug Synergism; D007167:Immunotherapy; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011713:Pyran Copolymer / Q000627:therapeutic use
D016861:Cyclooxygenase Inhibitors; D011713:Pyran Copolymer; D007213:Indomethacin