Enhancing Photodynamic Therapy with COX-2 Inhibition

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）治疗实体肿瘤的疗效。PDT在各种恶性肿瘤的临床治疗中仍然是有用的。然而，该方法尚未得到优化，肿瘤可能会复发。该应用的基本原理建立在最近的初步数据之上，该数据表明，使用环氧化酶-2 （COX-2）抑制剂的组合方式可以提高PDT的有效性。COX-2是类前列腺素生物合成中的一种限速酶，在许多肿瘤中表达。研究表明，COX-2的表达与肿瘤存活、增殖和/或血管生成有关。肿瘤中COX-2阳性表达也与临床预后不良相关。这些观察结果使科学家们开始评估COX-2特异性抑制剂在预防和治疗肿瘤中的作用。我们最初检测了PDT后小鼠肿瘤细胞的基因表达谱，观察到COX-2 mRNA增加了25倍。我们随后观察到，在非治愈性PDT治疗的肿瘤中，生物活性COX-2蛋白显著高于基础水平。这表明PDT治疗后逃避根除的肿瘤细胞可能表现出与COX-2过表达相关的促生存表型。我们的初步研究还表明，辅助使用COX-2选择性抑制剂可以改善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，而PDT联合COX-2选择性抑制剂将提高PDT的治疗反应性。为了更好地理解和优化这种新的联合模式方法，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被本提案中概述的研究证实，辅助COX-2抑制剂治疗可以为改善临床PDT提供一种安全有效的方法。

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.