Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Wiley - Tập 48 Số 6 - Trang 1742-1749 - 2003
Richard R. Renkiewicz1, Luping Qiu1, Charles A. Lesch1, Xin Sun1, Radhika Devalaraja1, Theresa Cody1, Eric Kaldjian1, Howard G. Welgus1, Vijaykumar M. Baragi1
1Pfizer Global Research & Development Ann Arbor Laboratories, Pfizer, Inc., Ann Arbor, Michigan

Tóm tắt

AbstractObjectiveTo characterize the clinical and histopathologic changes in a rat model of broad‐spectrum matrix metalloproteinase (MMP)–induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.MethodsMale Lewis rats weighing 150–180 gm were administered 10–30 mg of the broad‐spectrum MMP inhibitor marimastat over a 2‐week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.ResultsMarimastat‐treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high‐stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat‐treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.ConclusionThis simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.

Từ khóa


Tài liệu tham khảo

Powell WC, 1993, Expression of the metalloproteinase matrilysin in DU‐145 cells increases their invasive potential in severe combined immunodeficient mice, Cancer Res, 53, 417

10.1093/jnci/89.17.1260

10.1111/j.1749-6632.1998.tb10116.x

10.1200/JCO.2000.18.5.1135

10.1101/gad.815400

10.1016/S0092-8674(00)80064-1

Ito A, 1996, Degradation of interleukin‐1 beta by matrix metalloproteinases, J Biol Chem, 27, 14657, 10.1074/jbc.271.25.14657

10.1038/90100

10.1042/bj3220809

10.1359/jbmr.1998.13.1.59

Schedin P, 2000, Fibronectin fragments induce MMP activity in mouse mammary epithelial cells: evidence for a role in mammary tissue remodeling, J Cell Sci, 113, 795, 10.1242/jcs.113.5.795

10.1016/S0092-8674(00)81169-1

10.1016/S0065-7743(08)60463-7

10.1016/S0065-7743(08)61078-7

10.1046/j.1365-2036.1999.00633.x

10.1111/j.1749-6632.1999.tb07688.x

10.1302/0301-620X.80B5.8464

10.1016/S0959-8049(99)00007-6

BeckettRP WhittakerM MillerA MartinFM.The compound N′‐ [2 2‐dimethyl‐1S‐(pyridin‐2‐ylcarbamoyl)‐propyl]‐N4‐hydroxy‐2R‐isobutyl‐3S‐methoxy‐succinamide is a matrix metalloproteinase inhibitor. International Publication Number WO 99/25693 (British Biotech Pharmaceuticals Ltd.) 1997.

Nemunaitis J, 1998, Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer‐term studies, Clin Cancer Res, 4, 1101

10.1200/JCO.1998.16.6.2150

LevittNC EskinsF PropperDJ.A phase one pharmacokinetic study of CGS27023A a matrix metalloproteinase inhibitor. Proceedings of 34th Annual Meeting of the American Society of Clinical Oncology; 1998 May 16–19; Los Angeles (CA); 17:213A.

WildingG SmallE CollierM.A phase I pharmacokinetic evaluation of the matrix metalloproteinase inhibitor AG3340 in combination with mitoxantrone and prednisone in patients with advanced prostate cancer. Proceedings of 35th Annual Meeting of the American Society of Clinical Oncology; 1999 May 15–18; Atlanta (GA); 18:323A.

Millar A, 1996, 360 patient meta‐analysis of studies of marimastat: a novel matrix metalloproteinase inhibitor, Ann Oncol, 7, 123

10.2165/00003495-200059050-00002

Wood ND, 1996, The tolerability and pharmacokinetics of the cartilage protective agent (Ro32‐3555) in healthy male volunteers, Br J Clin Pharmacol, 42, 676

10.1021/jm990377j

10.1002/art.1780330312

10.1111/j.1749-6632.1994.tb24793.x

Boyle DL, 2001, Anti‐inflammatory effects of ABT‐702, a novel non‐nucleoside adenosine kinase inhibitor, in rat adjuvant arthritis, J Pharmacol Exp Ther, 296, 495

10.1002/(SICI)1097-0177(199907)215:3<190::AID-AJA2>3.0.CO;2-B

10.1177/002215540205000304

10.1359/jbmr.2000.15.1.82

10.1359/jbmr.2001.16.3.511

10.1359/jbmr.2000.15.11.2154

10.1007/s002230010032

10.1073/pnas.060037197

Thông tin
Thông tin xuất bản

Wiley

Tập 48 Số 6

1742-1749

Thông tin tác giả