Krüger Achim, Arlt Matthias J E, Gerg Michael, Kopitz Charlotte, Bernardo M Margarida, Chang Mayland, Mobashery Shahriar, Fridman Rafael
Institut für Experimentelle Onkologie und Therapieforschung der Technischen Universität München, Munich, Germany.
Cancer Res. 2005 May 1;65(9):3523-6. doi: 10.1158/0008-5472.CAN-04-3570.
Matrix metalloproteinases (MMPs), and in particular gelatinases (MMP-2 and MMP-9), play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in cancer patients have been disappointing. Whereas many reasons have been postulated to explain the failure of the clinical trials, lack of inhibitor selectivity was a major limitation. Thus, despite the consensus opinion that MMP-mediated proteolysis is essential for cancer progression and that certain MMPs represent important targets for intervention, effective and selective inhibition of those MMPs remains a major challenge in drug development. We previously reported the first mechanism-based MMP inhibitor, designated SB-3CT, which is a selective gelatinase inhibitor. Here we report that SB-3CT (5-50 mg/kg/d) is a potent inhibitor of liver metastasis and increases survival in an aggressive mouse model of T-cell lymphoma. This study shows that mechanism-based inhibition of gelatinases represents a novel approach to inhibitor design that promises to be a successful anticancer therapy.
基质金属蛋白酶（MMPs），尤其是明胶酶（MMP-2和MMP-9），在癌症进展中起关键作用。然而，在癌症患者中测试MMP抑制剂的临床试验结果令人失望。尽管人们提出了许多原因来解释临床试验的失败，但抑制剂缺乏选择性是一个主要限制因素。因此，尽管人们普遍认为MMP介导的蛋白水解对于癌症进展至关重要，并且某些MMPs是重要的干预靶点，但有效且选择性地抑制这些MMPs仍然是药物开发中的一项重大挑战。我们之前报道了首个基于机制的MMP抑制剂，命名为SB-3CT，它是一种选择性明胶酶抑制剂。在此我们报告，SB-3CT（5 - 50毫克/千克/天）是肝转移的强效抑制剂，并且在侵袭性T细胞淋巴瘤小鼠模型中可提高生存率。这项研究表明，基于机制的明胶酶抑制代表了一种新型的抑制剂设计方法，有望成为一种成功的抗癌疗法。
