RETINOIDS & RECEPTORS IN BLADDER CANCER CHEMOPREVENTION

膀胱癌是世界上最严重的癌症之一。 发达国家常见的癌症 新增膀胱癌病例5万多例 在美国，每年有11,200人死于这种癌症。 States. 膀胱癌的发生与口腔癌前病变一样， 化学预防研究模型。 天然和合成的类维生素A已被 作为口腔肿瘤的化学预防剂和化学治疗剂进行了测试， 但这些维甲酸对膀胱癌的疗效并不理想 记录在案。 拟议研究的目的是探讨 使用天然或合成类维生素A预防和 治疗膀胱癌，并探讨维甲酸的机制 在这种情况下。 不同类维生素A对细胞生长的影响， 分化、凋亡和视黄酸受体（RARs）的表达 在膀胱癌细胞系和正常膀胱上皮细胞中， 将研究短期培养物。 假设是：a）类维生素A 部分通过诱导抑制膀胱癌细胞的生长， B）RARs，尤其是RARs B，在调节细胞凋亡的生长中起作用。 和膀胱癌细胞的分化;和C）一些受体是 在某些膀胱癌中下调， 体内类维生素A。 将通过满足以下条件来检验假设： 以下具体目的：1）评价不同维甲酸的作用 对正常膀胱上皮细胞和膀胱癌细胞生长和分化的影响 癌细胞通过检查形态学，细胞周期， 细胞角蛋白4、7、8、13、18和19; 2）确定 不同维甲酸对膀胱癌细胞凋亡的影响 通过使用DNA片段化，碘化丙啶染色， 末端脱氧核苷酸转移酶测定和组合的影响 RAR选择性和类维生素A X受体（RXR）选择性维甲酸对生长的影响 抑制和细胞凋亡，以发现可能的累加或协同作用， 这些化合物; 3）检查类维生素A受体的表达， 不同维甲酸对正常膀胱上皮细胞的诱导作用 和膀胱癌细胞的逆转录聚合酶链反应 反应和蛋白质印迹以确定受体之间的关系 表达和不同类维生素A的化学预防作用;以及4） 分析膀胱癌标本中维甲酸受体的表达 在用4-（羟基苯基）维A酰胺（4 HPR）进行化学预防之前和之后， 原位杂交和聚合酶链反应。 的结果予以 研究有望增加我们对 新型维甲酸在膀胱癌中的作用和潜在价值 化学预防

DESCRIPTION: (Applicant's Description) Bladder cancer is the 6th most common cancer in the developed world. More than 50,000 new cases of bladder cancer and 11,200 deaths from this cancer occur each year in the United States. Bladder carcinogenesis, like oral premalignancy, is an excellent model for chemopreventive study. Natural and synthetic retinoids have been tested as chemopreventive and chemotherapeutic agents against oral tumors, but the effects of these retinoids on bladder cancers are not well documented. The objective of the proposed study is to explore the feasibility of using natural or synthetic retinoids in the prevention and treatment Of bladder cancer and to investigate the mechanisms of retinoids in this setting. The effect of different retinoids on cell growth, differentiation, apoptosis, and expression of retinoic acid receptors (RARs) in bladder cancer cell lines and normal bladder epithelial cells in short-term cultures will be studied. The hypotheses are: a) retinoids inhibit the growth of bladder cancer cells partially through the induction of apoptosis; b) RARs, especially RARB, play a role in regulating the growth and differentiation of bladder cancer cells; and C) some receptors are down-regulated in certain bladder cancers and can be up-regulated by retinoids in vivo. The hypotheses will be examined by fulfilling the following specific aims: 1) to evaluate the effects of different retinoids on growth and differentiation in normal bladder epithelial cells and bladder cancer cells by examining morphology, cell cycle, and the expression of cytokeratins 4, 7, 8, 13, 18, and 19 using western blotting; 2) to determine the effects of different retinoids on the induction of apoptosis in bladder cancer cells by using DNA fragmentation, propidium iodide staining, and terminal deoxynucleotidyl transferase assays and the effects of combinations of RAR-selective and retinoid X receptor (RXR)-selective retinoids on growth inhibition and apoptosis to find possible additive or synergistic actions of these compounds; 3) to examine the expression of retinoid receptors and their induction by different retinoids in normal bladder epithelial cells and bladder cancer cells by using reverse-transcriptase polymerase chain reaction and western blotting to determine the relationship between receptor expression and the chemopreventive effect of different retinoids; and 4) to analyze the expression of retinoid receptors in bladder cancer specimens before and after chemoprevention with 4-(hydroxyphenyl)retinamide (4HPR) by in situ hybridization and polymerase chain reaction. The results of these studies are expected to increase our understanding of the mechanisms of action and potential usefulness of new retinoids in bladder cancer chemoprevention.