Abstract
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.
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Acknowledgements
We thank Drs. Guy Salvesen and Jeffrey W. Smith for critical reading of the manuscript, and Dr. Daniel Rajotte and Jason A. Hoffman for helpful suggestions. This work was supported by grant CA74238 (E.R.) and Cancer Center Support grant CA30199 from the National Cancer Institute, grants DAMD17-98-1-8041 (R.P.) and DAMD17-98-1-8164 (W.A.) from the Department of Defense, and grants from the Academy of Finland, Finnish Dental Society, Finnish Cancer Society, and Sigrid Juselius Foundation (E.K. and C.G.G.). W.A. is the recipient of a CaP CURE award.
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Koivunen, E., Arap, W., Valtanen, H. et al. Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol 17, 768–774 (1999). https://doi.org/10.1038/11703
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DOI: https://doi.org/10.1038/11703
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