title: Potent farnesyltransferase inhibitor ABT-100 abrogates acute allograft rejection.
abstract: BACKGROUND
  Farnesyltransferase inhibitors (FTIs) inhibit the function of Ras, a GTPase involved in carcinogenesis and T cell activation. We evaluated the in vitro and in vivo immunomodulatory properties of a rationally designed FTI, ABT-100.
  
  
  METHODS
  The effects of ABT-100 on human peripheral blood mononuclear cell (PBMC) proliferation and the expression of the T cell activation markers CD25 and CD69 were studied. In a Wistar to Lewis rat heterotopic cardiac transplant model, ABT-100 was orally dosed alone or with a subtherapeutic course of cyclosporine (CsA). The degree of graft immune cell infiltrate was determined.
  
  
  RESULTS
  ABT-100 potently inhibited PBMC proliferation, but did not decrease expression of CD25 and CD69 during activation. Treatment with 25, 50 and 100 mg/kg ABT-100 BID increased allograft mean survival time (MST) to 12.8+/-3 days, 13.5+/-5 days and 13.8+/-3 days, respectively (vs 6.5+/-3 days for controls, p<0.001 by log rank). A subtherapeutic course of CsA increased MST to 12.7+/-3 days (p<0.001 vs control). Combination with ABT-100 at 25 and 100 mg/kg BID improved MST to 18.7+/-5 days and 19.5+/-4 days (both p<0.001 vs control and respective monotherapy groups). ABT-100 treatment at 100 mg/kg BID significant decreased the amount of graft infiltrate (2.5+/-4 mononuclear cells/high power field (hpf) vs 29+/-11 cells/hpf, p<0.001).
  
  
  CONCLUSIONS
  This is the first report that a specific FTI delays the development of acute rejection and supports the strategy of inhibiting Ras to impart immunomodulation. The antirejection and anticarcinogenic effects make FTIs a potentially useful adjunct in the antirejection regimens of malignancy-prone organ transplant recipients.
authors.affiliation: UCI Transplantation Laboratory, Department of Surgery, University of California Irvine College of Medicine, Irvine, California 92868, USA.
authors.forename: Ming-Sing
authors.initials: MS
authors.lastname: Si
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kwok
authors.forename: Jamie
authors.initials: J
authors.lastname: Kusumoto
authors.forename: Eric
authors.initials: E
authors.lastname: Naasz
authors.forename: Shi-Chung
authors.initials: SC
authors.lastname: Ng
authors.forename: David K
authors.initials: DK
authors.lastname: Imagawa
mesh_terms: D000208:Acute Disease; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007093:Imidazoles / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: C503142:ABT-100; D007093:Imidazoles; D007166:Immunosuppressive Agents; D051231:Farnesyltranstransferase; D018631:ras Proteins