Promotion of PDT Induced phototoxicity by bile acids

胆汁酸促进 PDT 诱导的光毒性

• 批准号: 6515220
• 负责人: David Harry Kessel
• 金额: $ 31.36万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515220
• 关键词: BCL2 gene /protein; Bax gene /protein; analog; apoptosis; breast neoplasms; chemical structure function; cholanate compound; fibrosarcoma; laboratory mouse; membrane potentials; mitochondrial membrane; neoplasm /cancer photoradiation therapy; nonhuman therapy evaluation; pharmacokinetics; photosensitizing agents; ursodeoxycholate

DESCRIPTION (provided by applicant): Our studies on mechanisms of cell death after photodynamic therapy (PDT) have suggested a novel procedure for enhancing phototoxic efficacy. We had previously shown that photodynamic damage to mitochondria catalyzes release of cytochrome c into the cytosol, triggering an apoptotic response. This can bypass defective steps in the apoptotic program elicited by conventional chemotherapy. Several recent reports have indicated that the bile acid ursodeoxycholic acid (UDCA) could protect the mitochondrial membrane of hepatoma cells from the pro-apoptotic effects of several agents including ethanol, deoxycholic acid, hydrogen peroxide and cadmium ion. We expected that UDCA would also protect mitochondria, an important PDT target, from the induction of an apoptotic response after PDT. We found instead the opposite effect: a significant promotion of cytochrome c release, caspase-3 activation and apoptotic cell death. This was demonstrated in both murine leukemia and hepatoma lclc7 cells. In the former cell line, we also demonstrated that UDCA could promote the apoptotic response to photosensitizing agents that catalyze selective photodamage to the anti-apoptotic protein Bcl-2, but do not affect the pro-apoptotic protein Bax. In a pilot study, we found the lifespan of mice bearing the RIF tumor was enhanced when UDCA was administered before irradiation, using the tin etiopurpurin SnET2 as the photosensitizing agent. These results are of potentially great clinical significance since UDCA is widely used for the treatment of gallstones and liver diseases, and its pharmacology and safety have been well established. To provide information on the pertinent mechanisms, we plan to [1] characterize the effects of UDCA on the cytotoxic responses to a spectrum of photosensitizing agents, [2] assess the structure-activity relationships in a series of UDCA analogs including the glycine- and taurine-conjugates that are formed in vivo, [3] examine the efficacy of UDCA for PDT enhancement in a variety of tumor cell lines, [4] measure PDT-promotion by UDCA and selected analogs in animal tumor models. Our hypothesis is that UDCA partitions into mitochondrial membranes and both lowers the threshold of photodamage, while offering protection from the chaotropic effects of more hydrophobic bile acids. Aim [4] will be carried out in a sub-contract with the PDT facility at University of Louisville where there is the required expertise in animal PDT studies. If the results of preliminary studies are borne out by further investigation, UDCA could offer a safe and effective means for promoting clinical PDT efficacy.

描述（由申请人提供）：我们对细胞死亡机制的研究 光动力疗法（PDT）后，提出了一种新的程序， 光毒性效应我们以前已经证明，光动力损伤， 线粒体催化细胞色素c释放到细胞质中， 凋亡反应这可以绕过凋亡程序中的缺陷步骤 是由常规化疗引起的。最近的几份报告表明， 胆汁酸熊去氧胆酸（UDCA）可保护线粒体 几种药物的促凋亡作用对肝癌细胞膜的影响 包括乙醇、脱氧胆酸、过氧化氢和镉离子。我们 预计UDCA也将保护线粒体，一个重要的PDT靶点， PDT后诱导凋亡反应。我们发现， 相反的作用：显著促进细胞色素c的释放，caspase-3 活化和凋亡性细胞死亡。这在两种小鼠中均得到证实。 白血病和肝癌LCLC 7细胞。在前一种细胞系中，我们还 表明UDCA可促进光敏化诱导的细胞凋亡反应， 催化抗凋亡蛋白Bcl-2的选择性光损伤的试剂， 但不影响促凋亡蛋白Bax。在一项试点研究中，我们发现 UDCA给药后，RIF荷瘤小鼠的寿命延长 照射前，以锡黄嘌呤SnET 2为光敏剂， 剂这些结果具有潜在的重大临床意义，因为UDCA 广泛用于治疗胆结石和肝病， 药理学和安全性已经得到很好的确立。提供资料说明 相关机制，我们计划[1]描述UDCA对 对一系列光敏剂的细胞毒性反应，[2]评估 一系列UDCA类似物（包括 甘氨酸-和牛磺酸-共轭物在体内形成，[3]检查 UDCA在多种肿瘤细胞系中增强PDT的功效，[4] 在动物肿瘤模型中测量UDCA和选定类似物的PDT促进作用。我们 一种假设是UDCA分配到线粒体膜， 光损伤的阈值，同时提供保护， 更疏水的胆汁酸的影响。[14]将在一个 与路易斯维尔大学PDT设施的分包合同， 动物PDT研究所需的专业知识。如果初步结果 研究证实，进一步的调查，UDCA可以提供一个安全， 促进PDT临床疗效的有效手段。