文章：

癌症中MMP抑制策略：试验后时代的创新

Strategies for MMP inhibition in cancer: innovations for the post-trial era

原文发布日期：2002-09-01

DOI: 10.1038/nrc884

类型: Review Article

开放获取: 否

要点：

1. The 24 human matrix metalloproteinases (MMPs) degrade all the main protein components of the extracellular matrix and basement membrane; are overexpressed in human tumours; and were originally associated with peritumour tissue degradation and metastasis formation. As MMPs are promising therapeutic targets, an intensive drug discovery programme led to many clinical trials of MMP inhibitors (MMPIs) for cancer therapy. However, until very recent reports of success in gastric carcinoma, these trials have largely been disappointing.
2. Many MMPs have been identified over the past two decades and these enzymes are now known to be mediators of a number of important normal cell processes. MMPs are involved in the early stages of cancer, explaining the failure of many of the MMPIs in late-stage cancer clinical trials.
3. A greater understanding of the regulatory mechanisms that control MMP transcription, activation and inhibition provides several new avenues for therapeutic intervention. Many new drugs are designed to target these key regulatory points.
4. MMP gene transcription can be inhibited by targeting extracellular factors or their cognate cell-surface receptors, signal-transduction pathways and nuclear factors that activate expression of these genes. MMP activation can also be inhibited by targeting proteases that cleave and activate MMPs.
5. New classes of inhibitors that mask MMP substrate cleavage sites or block the substrate-binding exosites, MMP-activatable cytotoxics and gene-targeting strategies offer alternative approaches for MMP inhibition in cancer.
6. Degradomic techniques can be developed to profile the protease expression pattern in tumours. Degradomic monitoring of the tumour should be complemented by use of surrogate markers for assessment of in vivo MMP activity and inhibition during treatment. However, the lack of practical surrogate markers that are available now is a problem that urgently needs addressing to improve the specificity and clinical efficacy of MMPI-based therapies.

要点翻译：

1. 人类24种基质金属蛋白酶（MMPs）能够降解细胞外基质和基底膜的所有主要蛋白质成分，在人类肿瘤中过度表达，最初被认为与肿瘤周围组织降解和转移形成相关。由于MMPs是极具潜力的治疗靶点，密集的药物研发计划推动了多项MMP抑制剂（MMPIs）用于癌症治疗的临床试验。但除近期胃癌治疗取得成功的报道外，这些试验大多未能达到预期效果。
2. 过去二十年中，许多MMP已被鉴定出来，目前已知这些酶是多种重要正常细胞过程的介质。MMPs参与癌症早期发展阶段，这解释了许多MMPI在晚期癌症临床试验中失败的原因。
3. 对控制MMP转录、激活和抑制的调控机制的深入理解，为治疗干预提供了若干新途径。许多新药的设计正是针对这些关键调控点。
4. 可通过靶向细胞外因子或其同源细胞表面受体、信号转导通路以及激活这些基因表达的核因子来抑制MMP基因转录；也可通过靶向切割并激活MMPs的蛋白酶来抑制其活化。
5. 新型抑制剂通过掩盖MMP底物切割位点或阻断底物结合外位点、MMP可激活的细胞毒性药物以及基因靶向策略，为癌症治疗中MMP抑制提供了替代方案。
6. 可开发降解组学技术来分析肿瘤中蛋白酶的表达模式。对肿瘤的降解组学监测应辅以替代标志物的使用，以评估治疗过程中体内MMP的活性和抑制情况。然而，目前缺乏可行的替代标志物是亟待解决的问题，这将有助于提高基于MMPI疗法的特异性和临床疗效。

英文摘要：

For more than two decades, the view that tumour-associated matrix metalloproteinases (MMPs) were required for peritumour tissue degradation and metastasis dominated the drive to develop MMP inhibitors as anticancer therapeutics. Until recently, clinical trials with MMP inhibitors have yielded disappointing results, highlighting the need for better insight into the mechanisms by which this growing family of multifunctional enzymes contribute to tumour growth. It is now recognized that MMP activity is tightly regulated at several levels, providing new avenues for blocking these enzymes. What are the different approaches that can be used to target MMPs, and which of these might lead to new therapeutic strategies for cancer?

摘要翻译： 

二十多年来，人们一直认为肿瘤相关基质金属蛋白酶（MMPs）在肿瘤周围组织降解和转移中起关键作用，这一观点推动了对MMP抑制剂作为抗癌治疗药物的研发。直到最近，MMP抑制剂的临床试验结果仍令人失望，这凸显了人们需要更深入地了解这一多功能酶家族促进肿瘤生长的机制。目前认为，MMP活性在多个层面受到严格调控，为阻断这些酶提供了新途径。有哪些不同的方法可用于靶向MMPs？其中哪些可能为癌症带来新的治疗策略？

原文链接：

Strategies for MMP inhibition in cancer: innovations for the post-trial era