The basis of this renewal is the hypothesis that certain bladder carcinogens are activated in the bladder by the hydroperoxidase component of prostaglandin endoperoxide synthetase (PES). Criteria are proposed to form the basis for testing the hypothesis. They are: PES-catalyzed metabolism of 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT) and N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) occurs in vivo and in intact tissue. Appropriate metabolic pathways should be demonstrated in susceptible species and organs. Compounds which inhibit PES-catalyzed metabolism of FANFT and ANFT will prevent FANFT-induced bladder cancer. The intermediate in PES-catalyzed ANFT metabolism is reactive. Urinary metabolites of FANFT will be characterized following FANFT feeding in the rat. Characterization will be facilitated by liquid chromatography with electrochemical detection, fast-atom bombardment mass spectrometry and comparison to known synthetic standards. An in vitro and in vivo screen will select compounds which inhibit PES-catalyzed metabolism of carcinogens, but do not inhibit promotion. Both aspirin and compounds which pass this screen will be examined for their ability to inhibit urinary excretion of PES metabolites. Metabolism of ANFT will be examined in intact tissue. Dog and human tissues will be used to assess PES and other enzymatic pathways of xenobiotic metabolism. The latter experiments and those directed at assessing the metabolism of different 2-substituted thiazole analogues of FANFT by PES and nitroreductase will provide an explanation of the diverse species and organ specificity of these carcinogens. Nucleoside adducts will be identified for comparison with aromatic amine adducts and in preparation for intact tissue experiments. Effects of aspirin on initiation and promotion phases of FANFT carcinogenesis will be examined in the rat. This proposal will provide new focus and insight into the genesis of chemically-induced bladder cancer and a rationale approach to its prevention.
