Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor.
The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential.
Maekawa
R
R
Discovery Research Laboratories, Shionogi and Company, Ltd., Osaka, Japan.
Maki
H
H
Yoshida
H
H
Hojo
K
K
Tanaka
H
H
Wada
T
T
Uchida
N
N
Takeda
Y
Y
Kasai
H
H
Okamoto
H
H
Tsuzuki
H
H
Kambayashi
Y
Y
Watanabe
F
F
Kawada
K
K
Toda
K
K
Ohtani
M
M
Sugita
K
K
Yoshioka
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D008666:Metalloendopeptidases