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Enhancing Photodynamic Therapy with COX-2 Inhibition

通过 COX-2 抑制增强光动力疗法

基本信息

批准号：
7234259
负责人：
CHARLES Joseph GOMER
金额：
$ 31.39万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7234259
关键词：
5&apos Flanking Region Address Affect Anabolism Angiogenic Factor Apoptosis Apoptosis Regulator Apoptotic Biological Assay Cessation of life Clinical Clinical Treatment Combined Modality Therapy Complementary DNA Coxibs Data Dose EMSA Effectiveness Elements Elevation Enzymes Exhibits Gene Expression Genes Individual Knockout Mice Malignant Neoplasms Mediating Messenger RNA Methods Modality Molecular Molecular Profiling Monitor Mus Mutation NS-398 Normal tissue morphology Numbers Pathway interactions Phenotype Photochemotherapy Photosensitizing Agents Phototoxicity Pilot Projects Plasma Play Post-Transcriptional Regulation Prevention Principal Investigator Procedures Prostaglandins Protein Overexpression Proteins Rate Recurrence Reporter Role Schedule Scientist Skin Solid Neoplasm Therapeutic Tissues Treatment Efficacy Tumor Cell Line Tumor Tissue angiogenesis cancer cell celecoxib cyclooxygenase 2 density improved in vivo inhibitor/antagonist killings neoplastic cell novel outcome forecast programs promoter repaired response therapeutic effectiveness transcription factor tumor

项目摘要

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。