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）治疗实体瘤的疗效。PDT仍然可用于各种恶性肿瘤的临床治疗。然而，该手术尚未优化，可能发生肿瘤复发。该应用的基本原理建立在最近的初步数据基础上，这些数据表明使用环氧合酶-2（考克斯-2）抑制剂的联合治疗方法可以提高PDT的有效性。考克斯-2是前列腺素类生物合成的限速酶，在多种肿瘤中均有表达。研究表明，考克斯-2表达与肿瘤存活、增殖和/或血管生成相关。考克斯-2在肿瘤中的阳性表达也与不良的临床预后相关。这些观察结果使科学家们评估考克斯-2特异性抑制剂在预防和治疗肿瘤中的作用。我们首先检测了小鼠肿瘤细胞PDT后的基因表达谱，观察到考克斯-2 mRNA增加了25倍。我们随后观察到，生物活性考克斯-2蛋白在用非治愈性PDT剂量治疗的肿瘤中显著升高高于基础水平。这表明PDT治疗后逃避根除的肿瘤细胞可能表现出与考克斯-2过表达相关的促存活表型。我们的初步研究还表明，连续施用考克斯-2选择性抑制剂可提高PDT介导的肿瘤杀伤，这进一步表明考克斯-2表达可能是PDT疗效的重要决定因素。我们假设PDT介导的考克斯-2表达降低了治疗效果，并且PDT与考克斯-2选择性抑制剂组合将改善PDT的治疗反应性。为了更好地理解和优化这种新的联合治疗方法，我们提出了三个具体目标：（1）确定调节PDT介导的考克斯-2表达的分子机制，（2）确定考克斯-2抑制剂如何改善PDT肿瘤反应，（3）优化使用考克斯-2选择性抑制剂增强PDT疗效的程序。如果我们的初步研究结果得到证实，在这个建议中概述的研究，抑制性考克斯-2抑制剂治疗可能会提供一个安全和有效的方法，以改善临床PDT。

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.