title: Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295.
abstract: BACKGROUND
  Signal transduction through the platelet-derived growth factor (PDGF)/PDGF-receptor (PDGFR) system has been linked to vascular smooth muscle cell migration and proliferation leading to allograft vasculopathy. This study describes the effect of the tyrphostin AG-1295, a specific PDGFR tyrosine-kinase inhibitor, on neointimal formation in this disease.
  
  
  RESULTS
  Rat aortic allografts transplanted from dark agouti (RT1 ) donors to Wistar-Furth (RT1 ) recipients were assessed in a new treatment model for local drug delivery from polymeric carrier matrices precoated with AG-1295. Matrices were wrapped around the graft immediately after transplantation. The recipients received no background immunosuppression. At day 80 posttransplantation, intimal thickness in AG-1295-treated grafts was reduced when compared to controls (11.8+/-9.1% intimal thickness vs. 23.7+/-6.4% intimal thickness; P=0.042). This finding corresponded to inhibition of intimal PDGFR-beta expression in AG-1295-treated grafts at day 20 posttransplantation (P =0.029 vs. allogeneic controls).
  
  
  CONCLUSIONS
  The tyrphostin AG-1295 reduces neointimal formation in aortic allograft vasculopathy by inhibition of PDGFR-beta-triggered tyrosine phosphorylation. Local drug release of specific tyrosine-kinase inhibitors from perivascularly co-implanted polymeric carrier matrices is effective in the prophylaxis of allograft vasculopathy under selected experimental conditions.
authors.affiliation: Department of Cardiothoracic Surgery, Hannover Medical School, Hannover, Germany. Karck@thg.mh-hannover.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.forename: Rolf
authors.initials: R
authors.lastname: Meliss
authors.forename: Michael
authors.initials: M
authors.lastname: Hestermann
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Klaus
authors.initials: K
authors.lastname: Pethig
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Shmuel
authors.initials: S
authors.lastname: Banai
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
authors.forename: Ilia
authors.initials: I
authors.lastname: Fishbein
authors.forename: Michael
authors.initials: M
authors.lastname: Chorny
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous / Q000009:adverse effects; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology*; D014652:Vascular Diseases / Q000517:prevention & control*
chemical_list: C407689:6,7-dimethoxy-2-phenylquinoxaline; D004791:Enzyme Inhibitors; D020032:Tyrphostins; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta