BLADDER CANCER: METABOLISM OF CARCINOGENS & PREVENTION

我们建议继续定义启动过程中涉及的具体机制 由化学物质引起的膀胱癌。这个 选择N-[4-(5-硝基-2-呋喃)-2-噻唑基]甲酰胺(FANFT)模型 由于高发病率所允许的实验设计的灵活性 想要的损伤。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 输送高浓度的更接近脱甲酰化的 致癌物，Anft，到尿路上皮。2)代谢激活发生在 前列腺素H合成酶(PHS)a氧化Anft的尿路上皮细胞 可能的激活机制。其他途径也可能参与其中。3) 减少膀胱上皮细胞可获得的ANFT数量的药物， 防止膀胱中的激活和/或防止激活的中间体 结合DNA将降低FANFT诱导的膀胱癌的发生率。 FANFT-ANFT代谢和处置将由完整的大鼠和 豚鼠，分别为敏感和抗病物种 FANFT诱发的膀胱癌。将评估目标组织的新陈代谢 取自大鼠、人和豚鼠的尿路上皮细胞。组织分布， 共价结合和层析分离的代谢物 将通过使用14C和35S标记来促进测定 FANFT-ANFT。从大鼠肾中提纯的FANFT脱甲酰基酶将被 特色化的。小儿麻痹症患者尿路上皮细胞合成二十聚糖底物的研究 也将接受评估。生物评估将包括细胞 Anft及其载体的转化和尿路上皮细胞毒性评价 代谢物。体内方法将使用两阶段FANFT模型来 评价膳食因素对生理(尿液pH)和代谢的影响 (激活)FANFT启动的参数。每一组实验都将 通过选择会改变我们假设的代理来持续测试我们的假设 代谢和处置，改善致病过程。数据 从这次更新中获得的将对理论和 膀胱癌的实用方面。理论上的意义涉及到 在实践中确定启动过程中涉及的路径 其意义与制定预防的治疗策略有关。

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.