Promotion of PDT Induced phototoxicity by bile acids

胆汁酸促进 PDT 诱导的光毒性

• 批准号: 6369921
• 负责人: David Harry Kessel
• 金额: $ 31.67万
• 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/6369921
• 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(申请人提供)：我们对细胞死亡机制的研究 在光动力疗法(PDT)之后，已经提出了一种新的增强 光毒功效。我们之前已经证明了光动力损伤对 线粒体催化细胞色素c释放到胞浆中，触发 细胞凋亡反应。这可以绕过凋亡程序中有缺陷的步骤 由常规化疗引起。最近的几份报告表明 胆汁酸熊去氧胆酸(UDCA)对线粒体的保护作用 几种药物对肝癌细胞膜促凋亡作用的研究 包括乙醇、脱氧胆酸、过氧化氢和镉离子。我们 预计UDCA还将保护线粒体，这是PDT的重要靶点， 光动力疗法后诱导的细胞凋亡反应。相反，我们发现了 相反的作用：显著促进细胞色素c的释放，caspase-3 激活和凋亡细胞死亡。这一点在两只小鼠身上都有证明 白血病和肝癌LCLC7细胞。在前一种细胞系中，我们还 证明UDCA可促进光敏反应中的细胞凋亡 催化选择性光损伤抗细胞凋亡蛋白Bcl-2的试剂， 但不影响促凋亡蛋白Bax。在一项初步研究中，我们发现 应用UDCA可延长RIF肿瘤小鼠的生存时间 照射前，用锡绿紫蛋白SnET2作为光敏剂 探员。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，其 药理和安全性已经得到了很好的证实。提供有关以下内容的信息 相关的机制，我们计划[1]表征UDCA对 对一系列光敏剂的细胞毒性反应，[2]评估 一系列UDCA类似物的构效关系 在体内形成的甘氨酸和牛磺酸结合物，[3]检查 UDCA在多种肿瘤细胞系中增强PDT的疗效，[4] 在动物肿瘤模型中测量UDCA和选定的类似物对PDT的促进作用。我们的 假说是UDCA分裂成线粒体膜，两者都降低 光损伤的阈值，同时提供对杂乱的保护 更疏水的胆汁酸的影响。AIM[4]将在一个 与路易斯维尔大学的PDT设施签订分包合同，那里有 在动物光动力疗法研究方面所需的专业知识。如果初选的结果 进一步的研究证明，UDCA可以提供一种安全和 提高临床光动力疗法疗效的有效手段。