Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina O P, Heikkilä P, Kantor C, Gahmberg C G, Salo T, Konttinen Y T, Sorsa T, Ruoslahti E, Pasqualini R
Department of Biosciences, Division of Biochemistry, Viikinkaari 5, University of Helsinki, FIN-00014, Finland.
Nat Biotechnol. 1999 Aug;17(8):768-74. doi: 10.1038/11703.
Several lines of evidence suggest that tumor growth, angiogenesis, and metastasis are dependent on matrix metalloproteinase (MMP) activity. However, the lack of inhibitors specific for the type IV collagenase/gelatinase family of MMPs has thus far prevented the selective targeting of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) for therapeutic intervention in cancer. Here, we describe the isolation of specific gelatinase inhibitors from phage display peptide libraries. We show that cyclic peptides containing the sequence HWGF are potent and selective inhibitors of MMP-2 and MMP-9 but not of several other MMP family members. Our prototype synthetic peptide, CTTHWGFTLC, inhibits the migration of human endothelial cells and tumor cells. Moreover, it prevents tumor growth and invasion in animal models and improves survival of mice bearing human tumors. Finally, we show that CTTHWGFTLC-displaying phage specifically target angiogenic blood vessels in vivo. Selective gelatinase inhibitors may prove useful in tumor targeting and anticancer therapies.
多条证据表明，肿瘤生长、血管生成和转移依赖于基质金属蛋白酶（MMP）的活性。然而，由于缺乏针对MMPs中IV型胶原酶/明胶酶家族的特异性抑制剂，迄今为止，无法将MMP-2（明胶酶A）和MMP-9（明胶酶B）作为癌症治疗干预的选择性靶点。在此，我们描述了从噬菌体展示肽库中分离特异性明胶酶抑制剂的过程。我们发现，含有序列HWGF的环肽是MMP-2和MMP-9的强效且选择性抑制剂，但对其他几个MMP家族成员无抑制作用。我们的原型合成肽CTTHWGFTLC可抑制人内皮细胞和肿瘤细胞的迁移。此外，它能在动物模型中阻止肿瘤生长和侵袭，并提高荷人肿瘤小鼠的存活率。最后，我们表明展示CTTHWGFTLC的噬菌体在体内可特异性靶向血管生成血管。选择性明胶酶抑制剂可能在肿瘤靶向和抗癌治疗中发挥作用。
