Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291.
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-alpha, tumor necrosis factor-alpha 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 IC(50) 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.
Naglich
J G
JG
Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Princeton, New Jersey 08543-4000, USA.
Jure-Kunkel
M
M
Gupta
E
E
Fargnoli
J
J
Henderson
A J
AJ
Lewin
A C
AC
Talbott
R
R
Baxter
A
A
Bird
J
J
Savopoulos
R
R
Wills
R
R
Kramer
R A
RA
Trail
P A
PA
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles; D007797:Laminin; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D061965:Matrix Metalloproteinase Inhibitors; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009930:Organic Chemicals; D011509:Proteoglycans
D000970:Antineoplastic Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D011509:Proteoglycans; C059485:matrigel; C422302:N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide; D003094:Collagen