Leflunomide analogue FK778 is vasculoprotective independent of its immunosuppressive effect: potential applications for restenosis and chronic rejection.
BACKGROUND
Leflunomide (LFM) inhibits experimentally both acute and chronic allograft rejection. The inhibition of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis is suggested to be the major immunosuppressive mechanism. The mechanism of its vasculoprotective effect is not known, although it may be linked to inhibition of receptor tyrosine kinases (RTK). Here, we have investigated whether sufficient vasculoprotective effect could be obtained upon administration of FK778, a LFM analogue with shorter half-life, and compared the dose response with that of a known platelet-derived growth factor RTK inhibitor, imatinib, after endothelial injury in vivo.


RESULTS
Wistar rats were used for aorta denudations. The rats remained untreated or received either FK778 or imatinib (STI571) at decreasing oral doses from 10 mg/kg per day. Half of the animals in both treatment groups also received uridine to reverse DHODH activity. Morphometric analysis was done after 14 day follow-up. In the untreated group, moderate neointima formation was detected. FK778 almost completely inhibited intimal formation, with or without uridine addition (P<0.05). Imatinib also inhibited neointima formation (P<0.05), whereas exogenous uridine reversed its effect.


CONCLUSIONS
Our results demonstrate that FK778 inhibits neointima formation by way of a mechanism that is independent of DHODH inhibitory activity on vascular smooth muscle cell. Interestingly, the effect of imatinib was inhibited by uridine, suggesting that part of its action on vascular stenosis could be mediated through inhibition of pyrimidine synthesis.
Savikko
Johanna
J
Transplantation Laboratory, Haartman Institute and Helsinki University Central Hospital, Helsinki, Finland. johanna.savikko@helsinki.fi.
Von Willebrand
Eva
E
Häyry
Pekka
P
D000480:Alkynes; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D001808:Blood Vessels / Q000187:drug effects*; D003251:Constriction, Pathologic / Q000188:drug therapy; D000090722:Dihydroorotate Dehydrogenase; D006084:Graft Rejection / Q000188:drug therapy; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009570:Nitriles; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects; D014529:Uridine / Q000494:pharmacology; D014652:Vascular Diseases / Q000188:drug therapy
D000480:Alkynes; D020533:Angiogenesis Inhibitors; D001549:Benzamides; D000090722:Dihydroorotate Dehydrogenase; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D000068877:Imatinib Mesylate; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011505:Protein-Tyrosine Kinases; D014529:Uridine