CHEMOPREVENTION BY ISOTHIOCYANATES

Naturally occurring and synthetic isothiocyanates are among the most e ffective chemopreventive agents known. A wide variety of isothiocyanat es prevents cancer in the rat lung, mammary gland, esophagus, Liver, s mall intestine, colon, and bladder. Mechanistic studies have shown tha t this chemopreventive activity is due to favorable modification of ph ase I and phase II carcinogen metabolism, resulting in increased carci nogen excretion or detoxification and decreased carcinogen DNA interac tions. Most studies reported that the isothiocyanate must be present a t carcinogen exposure in order to effect tumorigenesis inhibition. Our studies focus on naturally occurring isothiocyanates phenethyl isothi ocyanate (PEITC) and benzyl isothiocyanate (BITC) as lung cancer inhib itors. These studies employed the major lung carcinogens in tobacco sm oke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a) pyrene (BaP). Combining chemopreventive agents that inhibit tumorigene sis by NNK and BaP in rodents may be effective in addicted smokers. PE ITC inhibits lung tumor induction by NNK in E-344 rats and A/J mice, w hile BITC inhibits BaP-induced lung tumorigenesis in A/J mice; combini ng the two inhibits lung tumorigenesis by combined NNK and BaP in A/J mice. PEITC selectively inhibits metabolic activation of NNK in the ro dent lung, while inducing glucuronidation of 4-(methylnitrosamino)-1-( 3-pyridyl)-1-butanol (NNAL), one of the major NNK metabolites. Thus, P EITC decreases DNA and hemoglobin adduct formation by NNK while increa sing the amounts of NNAL and its glucuronide excreted in the urine. Pr esently available data indicate that non-toxic doses of PEITC can inhi bit the metabolic activation and carcinogenicity of NNK in rat and mou se lung; BITC has similar effects on BaP activation and tumorigenicity in mouse lung. Thus, combinations of chemopreventive agents active ag ainst different carcinogens in tobacco smoke may be useful in the chem oprevention of lung cancer. (C) 1995 Wiley-Liss, Inc.