The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model
The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model
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DOI：
10.1158/0008-5472.can-04-0071
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发表时间：
2004-04-01
期刊：
影响因子：
11.2
通讯作者：
Gomer, CJ
中科院分区：
文献类型：
--
作者：
Ferrario, A;Chantrain, CF;Gomer, CJ
光动力疗法（PDT）的临床结果是有希望的;然而，可能发生肿瘤复发，因此，需要用于改善治疗功效的方法。PDT诱导肿瘤细胞死亡和微血管损伤以及血管生成、炎症和促生存分子的表达。联合抗血管生成药物或环氧合酶-2抑制剂与PDT的临床前研究显示了改善的治疗反应性（A. Ferrario等人，Cancer Res 2000;60：4066-9; A. Ferrario等人，Cancer Res 2002;62：3956-61）。在本研究中，我们评估了Photofrin介导的PDT在诱导基质金属蛋白酶（MMPs）和MMP活性调节剂表达中的作用。我们还使用小鼠乳腺肿瘤模型研究了合成的NIMP抑制剂Prinomastat在PDT后增强杀肿瘤活性的功效。免疫印迹分析的提取物从PDT治疗的肿瘤表现出强烈的表达MMPs和细胞外MMP诱导剂沿着的金属蛋白酶-1的组织抑制剂的表达减少。明胶酶谱和酶活性测定进行的蛋白质提取物从治疗的肿瘤证实了潜在的和酶活性形式的MMP-9的诱导。免疫组化分析表明，浸润的炎性细胞和内皮细胞是PDT后MMP-9表达的主要来源，而在肿瘤细胞中观察到的表达可忽略不计。普利诺司他的管理显着改善PDT介导的肿瘤反应（P = 0.02），而不影响正常皮肤光敏。我们的研究结果表明，PDT诱导MMP和MMP抑制剂的连续使用可以提高PDT肿瘤反应。
Photodynamic therapy (PDT) clinical results are promising; however, tumor recurrences can occur and, therefore, methods for improving treatment efficacy are needed. PDT elicits direct tumor cell death and microvascular injury as well as expression of angiogenic, inflammatory, and prosurvival molecules. Preclinical studies combining antiangiogenic drugs or cyclooxygenase-2 inhibitors with PDT show improved treatment responsiveness (A. Ferrario et al., Cancer Res 2000;60:4066-9; A. Ferrario et al., Cancer Res 2002;62:3956-61). In the present study, we evaluated the role of Photofrin-mediated PDT in eliciting expression of matrix metalloproteinases (MMPs) and modulators of MMP activity. We also examined the efficacy of a synthetic NIMP inhibitor, Prinomastat, to enhance tumoricidal activity after PDT, using a mouse mammary tumor model. Immunoblot analysis of extracts from PDT-treated tumors demonstrated strong expression of MMPs and extracellular MMP inducer along with a concomitant decrease in expression of tissue inhibitor of metalloproteinase-1. Gelatin zymography and enzyme activity assays performed on protein extracts from treated tumors confirmed the induction of both latent and enzymatically active forms of MMP-9. Immunohistochemical analysis indicated that infiltrating inflammatory cells and endothelial cells were primary sources of MMP-9 expression after PDT, whereas negligible expression was observed in tumor cells. Administration of Prinomastat significantly improved PDT-mediated tumor response (P = 0.02) without affecting normal skin photosensitization. Our results indicate that PDT induces MMPs and that the adjunctive use of an MMP inhibitor can improve PDT tumor responsiveness.