Therapeutic potential of tetracycline derivatives to suppress the growth of abdominal aortic aneurysms.
Abdominal aortic aneurysms (AAA) represent a potentially lethal disorder associated with aging and atherosclerosis. Although current management of AAA is predicted on early detection and elective surgical repair, routine screening for AAA is infrequent, because most AAA are too small to warrant repair when first detected and because there are no therapeutic approaches proven to suppress aneurysm expansion. Basic research on this problem suggests that chronic inflammation and increased local production of elastin-degrading proteinases play prominent roles in the process of aneurysmal degeneration. Members of the matrix metalloproteinases (MMP) family appear to be the most prominent elastases produced in human AAA, suggesting that unique therapeutic targets might exist for aneurysm disease. Studies using a representative animal model for AAA support this view, providing a means for further development of pharmacological approaches to suppress aneurysm expansion. Indeed, recent work indicates that tetracycline derivatives have the potential to interrupt the progressive connective tissue destruction that occurs in AAA, by virtue of their non-antimicrobial properties as MMP inhibitors, and they do so at clinically achievable dose schedules. These findings support the view that MMPs are potentially important pharmacotherapeutic targets in AAA and, moreover, that tetracyclines might be useful in suppressing aneurysm expansion in vivo. Because tetracycline derivatives offer a number of distinct advantages as MMP inhibitors for patients with small AAA, prospective clinical trials of this novel therapeutic strategy can be anticipated in the near future.
Thompson
R W
RW
Department of Surgery, Washington University School of Medicine, 9901B Wohl Hospital, St. Louis, Missouri 63110, USA.
Liao
S
S
Curci
J A
JA
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000737:chemistry / Q000627:therapeutic use*