BLADDER CANCER: METABOLISM OF CARCINOGENS & PREVENTION

我们建议继续界定启动的具体机制 化学诱发的膀胱癌 的 选择N-[4-（5-硝基-2-呋喃基）-2-噻唑基]甲酰胺（FANFT）模型 由于高发病率允许实验设计的灵活性， 所需病变的位置。 构成我们建议基础的假设是： 1)某些特定的生理和代谢功能负责 递送高浓度的更接近脱甲酰化的 致癌物ANFT到尿道炎。 2)代谢活化发生在 前列腺素H合酶（PHS）氧化ANFT的尿路上皮细胞a 可能的激活机制。 也可能涉及其他途径。 第三章 降低膀胱上皮可接近的ANFT量的药剂， 防止膀胱中的活化和/或防止活化的中间体 结合DNA将降低FANFT诱导的膀胱癌的发生率。 FANFT-ANFT代谢和处置将通过完整大鼠和动物模型进行评估。 豚鼠，分别对以下物质敏感和耐药的种属 FANFT诱发的膀胱癌。 将评估靶组织代谢 用来自大鼠、人和豚鼠的尿路上皮细胞。 组织分布， 共价结合和色谱分离代谢物 使用14C-和35S-标记的 FANFT-ANFT。 将从大鼠中纯化的肾FANFT脱甲酰基酶进行纯化。 表征了 PHS的尿路上皮细胞合成类花生酸底物 也将被评估。 生物学评估将包括细胞 ANFT及其对尿路上皮细胞的毒性评价 代谢物。 体内方法将使用两阶段FANFT模型， 评价饮食因素对生理（尿液pH值）和代谢的影响 FANFT启动的（激活）参数。 每一组实验将 不断测试我们的假设，通过选择代理人， 代谢和处置和改善致病过程。 数据 从这次更新中获得的将对理论和 膀胱癌的治疗方法 理论意义涉及到 确定涉及引发的途径， 重要性涉及预防治疗策略的发展。

We propose to continue defining specific mechanisms involved in initiation of chemically-induced bladder cancer. The N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) model was chosen because of flexibility in experimental design permitted by a high incidence of the desired lesion. Hypotheses forming the basis of our proposal are: 1) Certain specific physiologic and metabolic functions are responsible for the delivery of high concentrations of the more proximate deformylated carcinogen, ANFT, to urothelium. 2) Metabolic activation occurs in urothelial cells with oxidation of ANFT by prostaglandin H synthase (PHS) a likely mechanism of activation. Other pathways may also be involved. 3) Agents which decrease the amount of ANFT accessible to bladder epithelium, prevent activation in bladder and/or prevent activated intermediates from binding DNA will reduce the incidence of FANFT-induced bladder cancer. FANFT-ANFT metabolism and disposition will be assessed by intact rat and guinea pig, species susceptible and resistant, respectively, to FANFT-induced bladder cancer. Target tissue metabolism will be assessed with urothelial cells from rat, human and guinea pig. Tissue distribution, covalent binding and chromatographically separable metabolite determiantions will be facilitated by the use of 14C- and 35S-labeled FANFT-ANFT. Renal FANFT deformylase purified from rat will be characterized. Urothelial cell synthesis of eicosanoid substrates of PHS will also be assessed. Biologic assessment will include cell transformation and urothelial cell toxicity evaluation of ANFT and its metabolites. The in vivo method will use the two-stage FANFT model to evaluate effects of dietary factors on physiologic (urine pH) and metabolic (activation) parameters of FANFT initiation. Each set of experiments will continuously test our hypotheses by the selection of agents which alter metabolism and disposition and ameliorate pathogenic processes. Data obtained from this renewal will have a profound impact on theoretical and practical aspects of bladder cancer. Theoretic signfiicance relates to determiation of pathways involved in initiation while practical significance relates to development of therapeutic strategies of prevention.