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.