RETINOIDS & RECEPTORS IN BLADDER CANCER CHEMOPREVENTION

描述：（申请人的描述）膀胱癌是第六大癌症 发达国家常见的癌症。 超过 50,000 例新发膀胱病例 在美国，每年有 11,200 人死于这种癌症 国家。 膀胱癌的发生，就像口腔癌前病变一样，是一个极好的癌变因素。 化学预防研究模型。 天然和合成的类视黄醇已被 作为口腔肿瘤的化学预防和化疗药物进行测试， 但这些类维生素A对膀胱癌的效果并不好 记录在案。 拟议研究的目的是探索 使用天然或合成类维生素A预防和治疗的可行性 膀胱癌的治疗及类维生素A作用机制的研究 在这个设置中。 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 (RAR) 的表达 在膀胱癌细胞系和正常膀胱上皮细胞中 将研究短期文化。 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 细胞凋亡； b) RAR，尤其是RARB，在生长调节中发挥作用 和膀胱癌细胞的分化； C) 一些受体是 在某些膀胱癌中下调，并且可以通过以下方式上调： 体内的类维生素A。 将通过满足以下条件来检验假设 具体目标如下：1）评估不同类维生素A的效果 对正常膀胱上皮细胞和膀胱的生长和分化的影响 通过检查形态、细胞周期和表达来检测癌细胞 使用蛋白质印迹法检测细胞角蛋白 4、7、8、13、18 和 19； 2）确定 不同类维生素A诱导膀胱细胞凋亡的作用 通过使用 DNA 片段化、碘化丙啶染色和 末端脱氧核苷酸转移酶测定和组合的效果 RAR 选择性和类视黄醇 X 受体 (RXR) 选择性类视黄醇对生长的影响 抑制和凋亡以寻找可能的相加或协同作用 这些化合物； 3) 检查类维生素A受体的表达和 它们在正常膀胱上皮细胞中被不同的类维生素A诱导 使用逆转录酶聚合酶链和膀胱癌细胞 反应和蛋白质印迹以确定受体之间的关系 不同类维生素A的表达和化学预防作用；和 4) 到 分析膀胱癌标本中视黄醇受体的表达 使用 4-(羟苯基)视黄酰胺 (4HPR) 进行化学预防之前和之后 原位杂交和聚合酶链反应。 这些结果 研究预计将增加我们对机制的理解 新型视黄醇在膀胱癌中的作用和潜在用途 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.