Enhancing Photodynamic Therapy with COX-2 Inhibition

描述(申请人提供)：我们建议的长期目标是提高光动力疗法(PDT)治疗实体肿瘤的疗效。光动力疗法继续用于各种恶性肿瘤的临床治疗。然而，该程序并未得到优化，肿瘤可能会复发。这一应用的基本原理建立在最近的初步数据基础上，该数据表明，使用环氧合酶-2(COX-2)抑制剂的联合方式可能会改善PDT的效果。COX-2是前列腺素生物合成的限速酶，在多种肿瘤中均有表达。研究表明，COX-2的表达与肿瘤的存活、增殖和/或血管生成有关。COX-2在肿瘤中的阳性表达也与临床预后不良有关。这些观察结果使科学家们评估了COX-2特异性抑制剂在肿瘤预防和治疗中所起的作用。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-2mRNA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，生物活性的COX-2蛋白显著高于基础水平。这表明，在PDT治疗后逃脱根除的肿瘤细胞可能表现出与COX-2过表达相关的支持生存的表型。我们的初步研究还表明，辅以COX-2选择性抑制剂可以提高PDT介导的肿瘤杀伤，这进一步表明COX-2的表达可能是PDT疗效的一个重要决定因素。我们假设，PDT介导的COX-2表达降低了治疗效果，PDT与COX-2选择性抑制剂联合使用将提高PDT的治疗反应性。为了更好地理解和优化这一新的组合方法，我们提出了三个具体目标：(1)确定调控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；(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这项建议中概述的研究证实，辅助性COX-2抑制剂治疗可能为改善临床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.