Skeletal Changes Associated with Matrix Metalloproteinase Inhibitors: Preclinical Safety Testing and Animal Model for Adverse Finding in Man

摘要

Matrix metalloproteinases are a family of zinc containing, calcium-dependent endopeptidases that have a wide variety of important physiological roles in tissue remodeling, tendon repair and maintenance, wound healing and ovulation (Hou 2003, Riley 2004,). They have also been implicated in pathological events such as cartilage degradation in arthritis, hypertension-associated cardiac fibrosis and the proteolytic events which occur during tumor invasion (Lopez, 2004, Rosenbaum, 2005). Inhibitors of matrix metalloproteinases have been sought to treat a wide variety of diseases, especially solid tumors, in which these enzymes are thought to play a role (Hoekstra, 2001) as well as for potential use in the treatment of osteoarthritis and rheumatoid arthritis. MMI270 is a hydroxamic acid derivative designed to act at the zinc-containing active site of matrix metalloproteinases. In this talk I plan to describe the skeletal changes in routine toxicology studies as well as musculoskeletal changes in an investigative study in which drug delivery was accomplished with alza pumps. It was perplexing that the fibroplastic changes observed in human cases had not been seen in animals treated with high doses in toxicology studies, with the exception of one report in marmosets (Wojtowicz-Praga, 1998).