BLADDER CANCER: CARCINOGENS AND PREVENTION

这种更新的基础是假设某些膀胱 致癌物在膀胱中被氢过氧化物酶成分激活。 前列腺素内过氧化合成酶(PES)。提出的标准是 形成检验假设的基础。它们是：PES催化的 2-氨基-4-(5-硝基-2-呋喃)-噻唑(ANFT)的代谢 N-[4-(5-硝基-2-呋喃)-2-噻唑基]甲酰胺(FANFT)存在于体内和体内 完整的组织。适当的代谢途径应该在 敏感的物种和器官。抑制PES催化的化合物 FANFT和Anft的代谢将预防FANFT诱导的膀胱癌。 PES催化的ANFT代谢的中间产物是反应性的。尿液 FANFT的代谢物将在FANFT喂食后进行表征 老鼠。将通过液相色谱来促进表征， 电化学检测、快原子轰击质谱仪和 与已知的合成标准进行比较。一种体内外筛选方法 将选择抑制PES催化的新陈代谢的化合物 致癌物质，但不抑制促进作用。阿司匹林和复方 通过这个筛查的人将被检查他们抑制的能力 尿中PES代谢物排泄。将检查Anft的新陈代谢 在完整的组织中。狗和人体组织将被用来评估PES和 异物代谢的其他酶途径。后一种实验 以及针对不同2-取代基代谢的评价 由PES和硝基还原酶合成的FANFT的噻唑类似物将提供 对这些物种的多样性和器官特异性的解释 致癌物质。核苷加合物将被鉴定，以便与 芳香胺加合物和为完整的组织实验做准备。 阿司匹林对FANFT起始期和促进期的影响 将在大鼠身上检测致癌作用。这项提议将提供新的 关注和洞察化学诱发膀胱癌的发生和发展 预防该病的基本方法。

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.