Preclinical and Clinical Studies of MMP Inhibitors in Cancer

Abstract

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.

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

“…Our results should be paralleled with the recently halted clinical development of some synthetic MMPIs due to the occurrence of severe side effects, including inflammatory polyarthritis, in cancer patients treated with such molecules [24,69]. In this context, it is worth noting that elevated MMP-9 levels were consistently reported in arthritic patients [70].…”

A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

“…38 This latter study also reported a decrease in ␣-smooth muscle actin expression in the presence of the MMP inhibitor. This blockade of contraction is difficult to dovetail with the reported side effects of some of these MMP inhibitors in clinical trials in which Duputyren's-like contracture and frozen shoulder were observed [13][14][15] ; however, this may reflect the fact that culture models of collagen lattice contraction only represent a single facet of a more complex disease process. Again, drawing on the analogy with liver fibrosis, a treatment that downregulates TIMPs but increases the activity of MMPs may be an appropriate therapy for DD.…”

“…12 The major side effect of these drugs was a so-called musculoskeletal syndrome, often referred to as musculoskeletal pain accompanied by tendonitis. 13,14 This was doseand time-dependent and reversible on treatment discontinuation, but did not respond well to nonsteroidal anti-inflammatory drugs or low-dose steroid treatment. The clinical presentation, when reported in detail, is described as frozen shoulder or a condition resembling DD.…”

Multiple changes in gene expression in chronic human Achilles tendinopathy

“…It is not clear which metalloproteases are involved since neither collagenase-nor gelatinasespecific inhibitors nor broad-spectrum MMP inhibitors with strong anti-sheddase action induced tendini-Ž . tis in a rat model Drummond et al, 1999 . Sheddase activity is one of the functions of the adamalysins, cell surface metalloproteases with properties of both ad-Ž .…”