The long-term objective of this project is to understand the mechanisms by which bladder cancers are induced so that factors which may be useful for interrupting the carcinogenic process can be identified. The immediate goal is to examine the hypothesis that benzidine may be activated by N-hydroxylation following monoacetylation, that urinary pH may affect bladder carcinogenesis by arylamines, that O-acetylation may be involved in carcinogenesis by 3, 2'-dimethyl-4-aminobiphenyl, that dietary factors, urinary pH and ions may affect bladder tumor promotion, and that oncogene expression may be associated with initiation and/or benzidine, N- hydroxy-N'-acetylbenzidine and its N-glucuronide, and the O- glucuronide of N-hydroxy-2-acetylaminoflurone in heteotopically transplanted bladders of the rat (HTB) will be determined. Effect of pH on the carcinogenicity of the N-glucuronide of N-hydroxy-2- aminofluorene will also be investigated in the HTB system. Using the unscheduled DNA synthesis system with urothelial cells (UDS system), chemicals that potentially can prevent bladder carcinogenesis by arylamines will be sought. Enzymatic derivatives of 3,2'-dimethyl-4-aminobiphenyl and 2-acetylaminofluorene. O- Acetyltransfer activities in various lobes of prostate glands of different strains of rats will be determined in order to establish the relationship between O-acetylation and carcinogenicity of N- hydroxy-3,2'-dimethyl-aminobiphenyl in this organ. An in vivo bioassay to examine modulation in the rat of the carcinogenesis of FANFT, and of the promoting activities of phenobarbital and sodium saccharin by Wayne diet and AIN-76A diet will be carried out. The relationship between promotion and urinary pH and ions in these animals will be examined. Utilizing molecular biological techniques, the temporal expression of Ha-ras and myc genes and mutation of Ha-ras in the urothelial cells of the rat following treatment with bladder carcinogens, promoters or uracil will be examined. All of these techniques are currently being utilized in this laboratory. The information provided will not only further our understanding of mechanisms of bladder carcinogenesis, it may also provide practical methods for the detoxification of arylamines resulting from inadvertent exposures.
