Modulation of rat mammary carcinogenesis by indomethacin

Indomethacin, a nonsteroidal antiinflammatory agent which inhibits prostaglandin biosynthesis, has significant activity in inhibiting the growth and/or inducing the regression of transplantable tumors. The present study was designed to determine if, in addition to its chemotherapeutic effects, indomethacin also acts as a cancer chemopreventive agent. Fifty-day-old virgin female Sprague-Dawley rats were given a single intragastric dose of either 8 or 16 mg of 7,12-dimethylbenz(a)anthracene (time 0). Basal diet was supplemented with 25 or 50 mg of indomethacin per kg of diet by the following protocol: (a) -2 to +1 week; (b) +1 week to end; or (c) none. Administration of indomethacin by both protocols resulted in an inhibition of mammary tumorigenesis; however, the effect of -2 to +1 week indomethacin exposure was primarily on the induction of benign mammary tumors, while +1 week to end indomethacin administration inhibited the induction of both benign mammary tumors and mammary cancers. These data indicate that indomethacin has significant protective activity when administered either during the "early" stage (comprising the carcinogen-target cell interaction) or the "late" stage (postcarcinogen tumor development) of mammary carcinogenesis in rats. Possible mechanisms of indomethacin action include both local and systemic effects.