NITRIC-OXIDE SYNTHASE AND SKIN TUMOR PROMOTION

Up-regulation of inducible form of nitric oxide (NO)-synthase and incr eased production of NO has been shown to occur in many pathological co nditions associated with inflammatory responses. In this study we show that topical application of skin tumor promoters, which are known to produce inflammatory response, down-regulate the constitutive form of NO-synthase in SENCAR mouse epidermis. The phorbol type of tumor promo ters viz 12-O-tetradecanoylphorbol-13-acetate (TPA) and mezerein produ ced greater inhibitory effects than the non phorbol tumor promoters vi z anthralin, n-dodecane, benzoyl peroxide and okadaic acid. Pretreatme nt of the skin with a polyphenolic fraction isolated from green tea, w hich possesses strong antioxidant activity, almost completely restored the inhibitory response. We suggest that the constitutive NO-synthase activity may play an important role in tumor promoter-caused oxidativ e burst during the promotion stage of multistage skin carcinogenesis, and that antioxidants may also target their anti-tumor promoting effec t via attenuating the NO-synthase pathway. (C) 1997 Academic Press.