Enhancing Photodynamic Therapy with COX-2 Inhibition

通过 COX-2 抑制增强光动力疗法

• 批准号: 6689681
• 负责人: CHARLES Joseph GOMER
• 金额: $ 33.11万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6689681
• 关键词: angiogenesis; apoptosis; combination chemotherapy; enzyme activity; gel mobility shift assay; gene expression; gene targeting; genetic transcription; genetically modified animals; immunocytochemistry; laboratory mouse; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; neoplastic growth; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; photosensitizing agents; prostaglandin endoperoxide synthase; protein binding; terminal nick end labeling; transfection /expression vector

DESCRIPTION (provided by applicant): The long-term objective of our proposal is to improve the efficacy of photodynamic therapy (PDT) for the treatment of solid tumors. PDT continues to be useful for the clinical treatment of a variety of malignancies. However, the procedure has not been optimized and tumor recurrences can occur. The rationale for this application builds upon recent preliminary data suggesting that a combined modality approach using a cyclooxygenase-2 (COX-2) inhibitor may improve PDT effectiveness. COX-2 is a rate-limiting enzyme in the biosynthesis of prostanoids and it is expressed in many tumors. Studies indicate that COX-2 expression is correlated with tumor survival, proliferation, and/or angiogenesis. Positive COX-2 expression in tumors has also been associated with poor clinical prognosis. These observations have led scientists to evaluate the role that COX-2 specific inhibitors can play in the prevention and treatment of tumors. We initially examined gene expression profiles following PDT in murine tumor cells and observed a 25 fold increase in COX-2 mRNA. We subsequently observed that biologically active COX-2 protein was significantly elevated above basal levels in tumors treated with non-curative PDT doses. This suggests tumor cells that escape eradication following PDT treatment may exhibit a pro-survival phenotype associated with COX-2 overexpression. Our pilot study also shows that adjunctive administration of a COX-2 selective inhibitor improves PDT mediated tumor killing, which further suggests that COX-2 expression may be an important determinant in PDT efficacy. We hypothesize that PDT mediated expression of COX-2 decreases treatment efficacy and that combining PDT with a COX-2 selective inhibitor will improve the therapeutic responsiveness of PDT. In order to better understand and optimize this novel combined modality approach we propose three specific aims: (1) to determine molecular mechanisms regulating PDT mediated COX-2 expression, (2) to determine how COX-2 inhibition improves PDT tumor response, and (3) to optimize procedures for enhancing PDT efficacy using a COX-2 selective inhibitor. If our preliminary findings are confirmed by studies outlined in this proposal, adjunctive COX-2 inhibitor treatment could provide a safe and effective method for improving clinical PDT.

描述（由申请人提供）：我们提案的长期目标是提高光动力疗法（PDT）治疗实体瘤的疗效。 PDT 继续用于多种恶性肿瘤的临床治疗。然而，该程序尚未优化，并且可能会发生肿瘤复发。该应用的基本原理基于最近的初步数据，表明使用环氧合酶-2 (COX-2) 抑制剂的组合方式方法可以提高 PDT 有效性。 COX-2是前列腺素生物合成中的限速酶，在许多肿瘤中表达。研究表明 COX-2 表达与肿瘤存活、增殖和/或血管生成相关。肿瘤中 COX-2 的阳性表达也与不良的临床预后相关。这些观察结果促使科学家评估 COX-2 特异性抑制剂在肿瘤预防和治疗中的作用。我们最初检查了小鼠肿瘤细胞中 PDT 后的基因表达谱，并观察到 ​​COX-2 mRNA 增加了 25 倍。我们随后观察到，在接受非治疗性 PDT 剂量治疗的肿瘤中，生物活性 COX-2 蛋白显着高于基础水平。这表明 PDT 治疗后逃脱根除的肿瘤细胞可能表现出与 COX-2 过度表达相关的促生存表型。我们的初步研究还表明，COX-2 选择性抑制剂的辅助给药可改善 PDT 介导的肿瘤杀伤，这进一步表明 COX-2 表达可能是 PDT 疗效的重要决定因素。我们假设 PDT 介导的 COX-2 表达会降低治疗效果，并且将 PDT 与 COX-2 选择性抑制剂相结合将改善 PDT 的治疗反应。为了更好地理解和优化这种新颖的组合方式方法，我们提出了三个具体目标：（1）确定调节 PDT 介导的 COX-2 表达的分子机制，（2）确定 COX-2 抑制如何改善 PDT 肿瘤反应，以及（3）优化使用 COX-2 选择性抑制剂增强 PDT 疗效的程序。如果我们的初步发现得到本提案中概述的研究的证实，辅助 COX-2 抑制剂治疗可以为改善临床 PDT 提供安全有效的方法。