ISOFLAVONE GENISTEIN INHIBITS THE INITIATION AND PROMOTION OF 2-STAGESKIN CARCINOGENESIS IN MICE

Isoflavone genistein is a specific inhibitor of protein tyrosine kinas e (PTK) and has been shown to have a variety of anticancer activities in cultured cells and animal models, We report here that genistein sig nificantly inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-initiated an d 12-O-tetradecanoyl phorbol-13-acetate (TPA)-promoted skin tumorigene sis in a two-stage carcinogenesis model. In an initiation study, 10 mu mol genistein was applied daily to female SENCAR mouse skin for 1 wee k, followed by initiation with 10 nmol DMBA. Mice were then treated wi th twice weekly 4 mu g TPA, Genistein was shown to reduce tumor incide nce and multiplicity in DMBA-initiated skin tumors by similar to 20 (P < 0.05) and 50% (P < 0.01), respectively, Two promotion studies were conducted using CD-1 and SENCAR mice. In experiment 1, CD-1 mice were initiated with 100 nmol DMBA and followed by a twice weekly regimen of 1 and 5 mu mol genistein/4 mu g TPA, In experiment 2, SENCAR mice wer e initiated with 10 nmol DMBA and followed by a regimen of 5, 10 and 2 0 mu mol genistein/2 mu g TPA, Both studies consistently showed that g enistein substantially inhibited TPA-promoted skin tumorigenesis by re ducing the tumor multiplicity by similar to 60 and 75%, respectively ( P < 0.01), However, the tumor incidence appeared to be less affected. Mechanistic studies showed that genistein inhibited DMBA-induced bulky DNA adduct formation and substantially suppressed TPA-stimulated H2O2 and inflammatory responses in mouse skin by >60% (P < 0.01). In contr ast, genistein only exhibited a moderate inhibition of TPA-induced orn ithine decarboxylase activity (P > 0.05), Our results suggest that gen istein exerts its anti-initiational and anti-promotional effects on sk in carcinogenesis probably through blockage of DNA adduct formation an d inhibition of oxidative and inflammatory events ill vivo.