Preclinical and clinical studies of MMP inhibitors in cancer.
The role of matrix metalloproteinases in tumor angiogenesis and growth is now well recognized for models of both human and animal cancer. Clinical studies currently under way with the prototype matrix metalloproteinase inhibitor, marimastat, will establish whether inhibitors of these enzymes are of benefit in the treatment of different types of human cancer. On chronic therapy in humans, marimastat induces a reversible tendinitis that can also be detected in certain animal species. This paper compares the ability of broad-spectrum and various types of selective matrix metalloproteinase inhibitors to induce tendinitis and to exhibit anticancer effects in an animal cancer model. Under conditions in which both systemic exposure and inhibitor potency are controlled, selective inhibitors are less pro-tendinitic, but are weaker anticancer agents than broad-spectrum agents such as marimastat. The clinical relevance of these findings is discussed.
British Biotech Pharmaceuticals Limited, Oxford, United Kingdom. drummond@britbio.co.uk
A H
AH
Drummond
P
P
Beckett
P D
PD
Brown
E A
EA
Bone
A H
AH
Davidson
W A
WA
Galloway
A J
AJ
Gearing
P
P
Huxley
D
D
Laber
M
M
McCourt
M
M
Whittaker
L M
LM
Wood
A
A
Wright
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D052256:Tendinopathy / Q000188:drug therapy
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D008666:Metalloendopeptidases