Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes.
Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes.
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DOI：
10.1158/1535-7163.mct-17-0646
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发表时间：
2018-06
影响因子：
5.7
通讯作者：
Mignatti P
中科院分区：
文献类型：
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作者：
Winer A;Adams S;Mignatti P
基质金属蛋白酶(MMPs)是一类降解细胞外基质多种成分的蛋白水解酶。大量的实验和临床证据表明，MMPs与肿瘤的侵袭、新生血管生成和转移有关，因此它们是肿瘤治疗的理想药理靶点。从1990年的S到2000年初的S，人们研究了基质金属蛋白酶的合成抑制剂(MMPIs)在不同癌症类型中的作用。出乎意料的是，尽管临床前数据前景看好，但所有试验在减轻肿瘤负担或提高总体存活率方面都未获成功；此外，MMPIs有不可预见的严重副作用。两个主要原因可以解释MMPI在临床试验中的失败。现在已经很明显，一些MMPs具有抗肿瘤作用；因此，最初试验中使用的广谱MMPi可能会阻断这些MMPs，导致肿瘤进展。此外，尽管MMPs参与了肿瘤进展的早期阶段，但MMPIs在晚期疾病患者中进行了测试，超过了这些化合物可能有效的阶段。随着更多特异性MMPI的问世，可以重新考虑将基质金属蛋白酶靶向用于癌症治疗；然而，应该设计新的试验来测试它们在早期肿瘤中的抗转移特性，终点应该关注于除减少转移肿瘤负担之外的其他参数。
The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis and metastasis, and therefore they represent ideal pharmacological targets for cancer therapy. From the 1990's to early 2000's synthetic inhibitors of MMPs (MMPIs) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have anti-tumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP-targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their anti-metastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden.