BLADDER CANCER: CARCINOGENS AND PREVENTION

这种更新的基础是假设某些膀胱 致癌物质在膀胱中被氢过氧化物酶成分激活 前列腺素内过氧化物合成酶（PES）。 建议的标准是 形成检验假设的基础。 它们是：PES催化的 2-氨基-4-（5-硝基-2-呋喃基）-噻唑（ANFT）的代谢， N-[4-（5-硝基-2-呋喃基）-2-噻唑基]甲酰胺（FANFT）在体内和体内均存在， 完整组织 适当的代谢途径应在 敏感的物种和器官。 抑制PES催化的化合物 FANFT和ANFT的代谢将防止FANFT诱导的膀胱癌。 PES催化的ANFT代谢的中间体是反应性的。 尿 FANFT的代谢物将在FANFT喂养后表征。 大鼠 将通过液相色谱法进行表征， 电化学检测、快原子轰击质谱和 与已知的合成标准进行比较。 体外和体内筛选 将选择抑制PES催化的代谢的化合物， 致癌物质，但不抑制促进。 阿司匹林和化合物 通过这个筛选的细胞将被检查其抑制 PES代谢物的尿排泄。 将检查ANFT的代谢 在完整的组织中。 犬和人体组织将用于评估PES， 异生物质代谢的其他酶途径。 后面的实验 和那些旨在评估不同2-取代的 通过PES和硝基还原酶的FANFT的噻唑类似物将提供 解释不同的物种和器官特异性，这些 致癌物质。 将鉴别核苷加合物，以与 芳族胺加合物和用于完整组织实验的准备。 阿司匹林对FANFT启动和促进时相的影响 将在大鼠中检查致癌作用。 该提案将提供新的 关注和洞察化学诱导的膀胱癌的发生， 一个合理的方法来预防它。

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.