Peptidomimetic antagonist of the integrin α(v)β3 inhibits leydig cell tumor growth and the development of hypercalcemia of malignancy

Christopher P. Carron, Debra M. Meyer, Jodi A. Pegg, V. Wayne Engleman, Maureen A. Nickols, Steven L. Settle, William F. Westlin, Peter G. Ruminski, G. Allen Nickols

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

The integrin α(v)β3 interacts with the arginine-glycine-aspartic acid (RGD) tripeptide recognition sequence of a variety of extracellular matrix proteins. Recent studies show that α(v)β3 plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of α(v)β3 inhibit angiogenesis processes that include endothelial cell adhesion and migration. Consequently, we reason that an RGD-based peptidomimetic antagonist of α(v)β3 might inhibit tumor angiogenesis and tumor growth in vivo. An RGD-peptidomimetic library was screened to identify antagonists of vitronectin binding to α(v)β3, and the compounds chosen were modified to produce selective and potent inhibitors of α(v)β3. One of these compounds, β[[2-2-[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]amino]acetyl]amino]- 3,5-dichlorobenzenepropanoic acid (SC-68448), inhibited vitronectin binding to both α(v)β3 and the closely related platelet receptor α(IIb)β3, in a dose-responsive manner. SC-68448 inhibited vitronectin binding to α(v)β3 (IC50, 1 nM) and fibrinogen binding to the platelet receptor α(IIIb)β3 (IC50, >100 Nm), demonstrating that SC-68448 was 100-fold more potent as an inhibitor of α(v)β3 versus α(IIb)β3. In cell-based studies, SC-68448 inhibited α(v)β3-mediated endothelial cell proliferation in a dose- dependent manner but did not inhibit tumor cell proliferation, suggesting that effects on endothelial cell proliferation were not due to SC-68448- induced cytotoxicity. In accord with these results, SC-68448 inhibited angiogenesis in vivo in a basic fibroblast growth factor-induced rat corneal neovascularization model. A xenogeneic severe combined immune deficiency mouse/rat Leydig cell tumor model was developed for testing SC-68448 as an inhibitor of tumor growth in vivo. Rat Leydig cell tumors grew rapidly in severe combined immune deficiency mice and produced humoral hypercalcemia of malignancy. SC-68448 inhibited the growth of the tumors in mice by up to 80% and completely blocked the development of hypercalcemia. Together, these results demonstrate the feasibility of antitumor therapies based upon the development of nontoxic small molecule pharmacological antagonists of integrin α(v)β3.

Original languageEnglish
Pages (from-to)1930-1935
Number of pages6
JournalCancer research
Volume58
Issue number9
StatePublished - May 1 1998

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