Effect of novel limited-spectrum MMP inhibitor XL784 in abdominal aortic aneurysms.
BACKGROUND
Inhibiting the growth of small abdominal aortic aneurysms (AAAs) is a clinically valuable goal and fills an important therapeutic void. Based on studies in animals and humans, inhibition of the activity of elastolytic matrix metalloproteinases (MMPs) has the potential to slow AAA expansion and limit morbidity and the need for surgery. Previous attempts to make use of the synthetic MMP inhibitors in the treatment of chronic conditions have been limited by intolerable side effects. The limited-spectrum synthetic MMP inhibitor, XL784, was well tolerated and devoid of side-effects associated with other nonspecific MMP inhibitors in phase I studies. We hypothesized that clinically relevant doses of XL784 would be effective at inhibiting aneurysm development in a mouse model.


METHODS
The 14-day elastase-perfusion model of AAA in mice was used. An initial screening study of XL784 (50 [n = 17], 125 [n = 17], and 250 mg/kg [n = 18]) administered via gavage daily until harvest. Controls received diluent alone (n = 18) or doxycycline in drinking water (n = 19). Aortic diameter was measured pre-perfusion (AD(pre)) and at harvest (AD(har)). A second study used XL784 (250 [n = 9]; 375 [n = 9], and 500 mg/kg [n = 14]) and diluent alone (n = 9) administered via gavage. The percentage dilatation [%ΔAD = [(AD(har) - AD(pre))/AD(pre)] ×100] was calculated and elastin and inflammatory content was scored.


RESULTS
All mice tolerated the treatments similarly. Control mice all developed aneurysms with a mean %ΔAD of 158.5% ± 4.3%. Treatment with all doses of XL784 and doxycycline were effective in inhibiting aortic dilatation. There was a clear dose-response relationship between XL784 and reductions in aortic dilatation at harvest (50 mg/kg 140.4% ± 3.2%; 125 mg/kg 129.3% ± 5.1%; 250 mg/kg 119.2% ± 3.5%; all Ps < .01 compared to control). This continued with the higher doses (375 mg/kg 88.6% ± 4.4%; 500 mg/kg 76.0% ± 3.5%). The highest 2 doses of XL784 tested were more effective than doxycycline (112.2% ± 2.0%, P < .05) in inhibiting maximal dilatation of the aorta after elastase perfusion.
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St Louis, MO, USA.
Terri
T
Ennis
Jianping
J
Jin
Sarah
S
Bartlett
Batool
B
Arif
Kathy
K
Grapperhaus
John A
JA
Curci
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001019:Aortic Rupture / Q000517:prevention & control; D004108:Dilatation, Pathologic / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism; D006207:Half-Life; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase; D011897:Random Allocation; D012720:Severity of Illness Index
D000894:Anti-Inflammatory Agents, Non-Steroidal; D061965:Matrix Metalloproteinase Inhibitors; D004549:Elastin; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2