RETINOIDS & RECEPTORS IN BLADDER CANCER CHEMOPREVENTION

描述：(应聘者描述)膀胱癌排在第六位 发达国家常见的癌症。超过5万例新的膀胱癌病例 美国每年发生癌症和11,200人死于这种癌症 各州。膀胱癌的发生，就像口腔癌前病变一样，是一个极好的 化学预防研究的模型。天然和合成的维甲酸一直是 被测试为口腔肿瘤的化学预防和化疗药物， 但是这些维甲酸对膀胱癌的效果并不好。 有记录在案。拟议研究的目的是探讨 使用天然或合成的维甲酸预防和预防 膀胱癌的治疗及维甲酸作用机制的研究 在这种情况下。不同的维甲酸对细胞生长的影响， 视黄酸受体(RARs)的分化、凋亡和表达 在膀胱癌细胞系和正常膀胱上皮细胞中 将对短期培养进行研究。假设是：a)维甲酸 部分通过诱导抑制膀胱癌细胞的生长 B)RARs，尤其是RARB，在调节生长中起作用 和膀胱癌细胞的分化；以及C)一些受体是 在某些膀胱癌中下调，并可通过 体内的维甲酸。这些假说将通过实现 具体目标如下：1)评估不同维甲酸的疗效 正常膀胱上皮细胞和膀胱的生长分化 通过检测肿瘤细胞的形态、细胞周期和细胞因子的表达 用免疫印迹法检测细胞角蛋白4、7、8、13、18和19； 不同维甲酸在诱导膀胱细胞凋亡中的作用 通过DNA碎裂、碘化丙啶染色和 末端脱氧核苷酸转移酶检测及其联合应用的影响 视黄酸受体和视黄醇X受体(RXR)选择性维甲酸对生长的影响 抑制和凋亡，以寻找可能的相加或协同作用 这些化合物；3)检测维甲酸受体和 不同维甲酸对正常膀胱上皮细胞的诱导作用 用逆转录聚合酶链法检测膀胱癌细胞 反应和Western blotting确定受体之间的关系 不同维甲酸的表达及化学预防作用；4) 膀胱癌组织中维甲酸受体的表达分析 4-(羟基苯基)维甲酰胺(4HPR)化学预防前后 原位杂交和聚合酶链式反应。这些研究的结果 研究有望增加我们对心力衰竭的机制的了解。 新型维甲酸在膀胱癌治疗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.