METABOLISM OF CHEMOPREVENTIVE RETINOIDS

维甲酸是一种有效的抗癌药物，可以抑制血管生成。 致癌前病变(增生、鳞状化生) 并导致上皮组织中预先形成的病变的消退。 13-顺式维甲酸显示出很强的化学预防活性 再加上动物研究中寄主毒性的降低。13-顺式-维甲酸 ACID目前正在对以下患者进行临床试验 可识别的上皮性癌症发生的高风险。展望未来 对于长期服用这种维甲酸需要一个详细的 其体内代谢的研究。此外，这种做法的后果 13-顺式维甲酸慢性治疗对大鼠肾小管上皮细胞生理代谢的影响 必须对内源性维甲酸进行评估。我们建议建立一只大鼠 慢性13-顺式维甲酸治疗模型，并利用该模型研究 这种维甲酸在体内的代谢。建议的目标 研究内容如下：1)13-顺式维甲酸代谢物的研究 长期用药大鼠视黄醇靶区组织中的酸；2) 化学结构的表征及其抗癌作用 这些代谢物的活性和3)效果的评价 慢性13-顺式维甲酸治疗对某些生理方面的影响 视黄醇代谢。新陈代谢研究将在 开发的高效液相色谱(HPLC)方法 维甲酸类化合物的分离。活体中的个体 13-顺式维甲酸的代谢产物将通过高效液相色谱分离纯化并鉴定 通过吸收光谱、质谱学、核磁共振 光谱学，一种化学合成。黄曲霉毒素的抗癌活性 代谢物将在两种维甲酸敏感的测试中进行测试：表皮 鸟氨酸脱羧酶活性测定与胚胎癌分化 化验。从代谢物结构关联中获得的信息 具有抗癌活性不仅有助于描绘体内的 13-顺式-维甲酸的代谢，但可以为设计 具有增强的化学预防活性的合成维甲酸，增加 生物半衰期，也许还有选择性定位。三个重要因素 维生素A动态平衡方面的研究也将在 13-顺式维甲酸处理的大鼠；肝脏维生素A储备，血清视黄醇 水平，以及视黄酸酯、视黄醇和 几个维生素A靶器官中的四丁酸。这些实验将 被用来观察慢性13-顺式维甲酸治疗对小鼠心脏功能的影响 内源性维甲酸的代谢。

Retinoids are potent anticarcinogenic agents which inhibit the formation of carcinogen induced preneoplastic lesions (hyperplasia, squamous metaplasia) and cause regression of preformed lesions in epithelial tissues. 13-cis-Retinoic acid has demonstrated potent chemopreventive activity coupled with diminished host toxicity in animal studies. 13-cis-Retinoic acid is currently undergoing clinical trials in individuals who are at identifiable high risk for development of epithelial cancers. The prospect for long-term administration of this retinoid necessitates a detailed investigation of its in vivo metabolism. Furthermore, the consequences of chronic 13-cis-retinoic acid therapy on the physiological metabolism of endogenous retinoids must be evaluated. We propose to establish a rat model of chronic 13-cis-retinoic therapy and to use this model to study the in vivo metabolism of this retinoid. The objectives of the proposed research are: 1) the investigation of the metabolites of 13-cis-retinoic acid in selected retinoid target-tissues of chronically treated rats; 2) the characterization of the chemical structure and anticarcinogenic activity of these metabolites and 3) the evaluation of the effects of chronic 13-cis-retinoic acid treatment on certain aspects of phy siological retinol metabolism. Metabolism studies will be conducted with high-performance liquid chromatography (HPLC) methods developed by the authors for the separation of retinoids. The individual in vivo metabolites of 13-cis-retinoic acid will be purified by HPLC and identified by absorbance spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy, an chemical synthesis. The anticarcinogenic activity of the metabolites will be tested in two retinoid-sensitive assays: the epidermal ornithine decarboxylase assay and the embryonal carcinoma differentiation assay. Information gained from the correlation of metabolite structure with anticancer activity would not only help to delineate the in vivo metabolism of 13-cis-RA, but could provide insight useful for the design of synthetic retinoids with enhanced chemopreventative activity, increased biological half-lives, and perhaps selective localization. Three important aspects of vitamin A homeostasis will also be investigated in 13-cis-retinoic acid treated rats; liver vitamin A stores, serum retinol levels, and the steady-state concentrations of retinyl esters, retinol, and tetinoic acid in several vitamin A-target organs. These experiments will be used to pobe the effects of chronic 13-cis-retinoic acid therapy on the metabolism of endogenous retinoids.