RT Journal Article
SR Electronic
T1 Inhibition of Angiogenesis and Metastasis in Two Murine Models by the Matrix Metalloproteinase Inhibitor, BMS-275291
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 8480
OP 8485
VO 61
IS 23
A1 Naglich, Joseph G.
A1 Jure-Kunkel, Maria
A1 Gupta, Elora
A1 Fargnoli, Joseph
A1 Henderson, Arris J.
A1 Lewin, Anne C.
A1 Talbott, Randy
A1 Baxter, Andy
A1 Bird, John
A1 Savopoulos, Ranjev
A1 Wills, Ruth
A1 Kramer, Robert A.
A1 Trail, Pamela A.
YR 2001
UL http://cancerres.aacrjournals.org/content/61/23/8480.abstract
AB BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteinase (MMP) inhibitor currently in clinical development for the treatment of cancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-α, tumor necrosis factor-α receptor, interleukin-6 receptor, or l-selectin. In vitro, BMS-275291 is a potent inhibitor (nm) of the activities of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC50 values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis. ©2001 American Association for Cancer Research.