TY - JOUR
T1 - Peptidomimetic antagonist of the integrin α(v)β3 inhibits leydig cell tumor growth and the development of hypercalcemia of malignancy
AU - Carron, Christopher P.
AU - Meyer, Debra M.
AU - Pegg, Jodi A.
AU - Engleman, V. Wayne
AU - Nickols, Maureen A.
AU - Settle, Steven L.
AU - Westlin, William F.
AU - Ruminski, Peter G.
AU - Nickols, G. Allen
PY - 1998/5/1
Y1 - 1998/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032080854&partnerID=8YFLogxK
M3 - Article
C2 - 9581835
AN - SCOPUS:0032080854
VL - 58
SP - 1930
EP - 1935
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 9
ER -