TNP-470, an angiogenesis inhibitor, attenuates the development of allograft vasculopathy.
Fischer 344 rat recipients of Lewis allografts were treated with TNP-470, a synthetic fumagillin derivative and a well-established angiogenesis inhibitor. TNP-470 alone resulted in some prolongation of graft survival as compared with untreated recipients, but all grafts ultimately failed. In contrast, treatment with cyclosporine (CsA) from day 0 to 30 resulted in prolonged graft survival and marked cardiac allograft vasculopathy (CAV) by histology (mean score 2.28+/-0.2). There were many neovessels within the intima of CAV lesions. When TNP-470 was administered in combination with CsA from day 0 to 30, the degree of CAV was similar to that with CsA alone (mean score 2.22+/-0.26). However, when TNP-470 was administered from day 30 to 120 after discontinuation of CsA, there was a marked reduction in the degree of CAV (mean score 1.08+/-0.11). Therefore, TNP-470 interrupts the progression of CAV when given late but does not prevent its development when given immediately posttransplantation.
Denton
Mark D
MD
Division of Nephrology, Department of Medicine, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Magee
Colm
C
Melter
Michael
M
Dharnidharka
Vikas R
VR
Sayegh
Mohamed H
MH
Briscoe
David M
DM
D000005:Abdomen; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003327:Coronary Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D003510:Cyclohexanes; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects; D008297:Male; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D016042:Transplantation, Heterotopic
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D016572:Cyclosporine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol