EFFECTS OF CHRONIC INDOMETHACIN THERAPY ON THE DEVELOPMENT AND PROGRESSION OF SPONTANEOUS MAMMARY-TUMORS IN C3H HEJ MICE/

The present study was designed to test the hypothesis that endogenous prostaglandin E (PGE) promotes the development, growth and metastasis of spontaneous mammary tumors in C3H/HeJ female retired breeder mice. The effect of chronic oral indomethacin (indo) therapy starting at 6 m onths of age was tested on these parameters as well as on animal survi val, in comparison with control mice placed on 0.2% ethanol in drinkin g water for up to 25 months of age. Indo treatment delayed the initial (up to 27 weeks) development of primary tumors by 11-12 weeks; howeve r, the subsequent rate of tumor appearance was unaffected (totaling 82 % in indo-treated vs. 90% in controls by 25 months of age). Spontaneou s regression of primary tumors (26% in controls) increased a-fold (53% ) with indo therapy. While the apparent reduction in the growth rate o f;primary tumors and the overall prolongation of animal survival were not significant, the lifespan of mice bearing multiple tumors was sign ificantly prolonged by therapy. There was also a 2-fold reduction in t he incidence of lung metastases in mice bearing detectable primary tum ors, and this was more pronounced during the earlier phase of tumor de velopment. Positive immunostaining for cyclooxygenase-2 enzyme (indica tive of the cellular source of PGE) was exhibited by tumor cells, stro mal cells and macrophages within the primary tumors. Tumors in indo-tr eated mice exhibited histological evidence of increased differentiatio n (acinar architecture), significant tumor cell death, mononuclear cel l infiltration and reduction in vascularity, indicating that the benef icial effects of indo were due to multiple mechanisms, including impro ved immune response and reduced angiogenesis. (C) 1997 Wiley-Liss, Inc .