title: Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.
abstract: OBJECTIVE
  To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100.
  
  
  METHODS
  In vitro sensitivity of a panel of human cell lines was determined using proliferation and clonogenic assays. In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics. Efficacy of the racemate of ABT-100 (A-367074) was also compared with R115777 (tipifarnib).
  
  
  RESULTS
  ABT-100 inhibited proliferation of cells in vitro carrying oncogenic H-Ras (EJ-1 bladder; IC(50) 2.2 nmol/L), Ki-Ras (DLD-1 colon, MDA-MB-231 breast, HCT-116 colon, and MiaPaCa-2 pancreatic; IC(50) range, 3.8-9.2 nmol/L), and wild-type Ras (PC-3 and DU-145; IC(50), 70 and 818 nmol/L, respectively) as well as clonogenic potential. ABT-100 shows 70% to 80% oral bioavailability in mice. ABT-100 regressed EJ-1 tumors (2-12.5 mg/kg/d s.c., every day for 21 days) and showed significant efficacy in DLD-1, LX-1, MiaPaCa-2, or PC-3 tumor-bearing mice (6.25-50 mg/kg/d s.c. once daily or twice daily orally). A-367074 showed equivalent efficacy to R115777 given at approximately one-fourth the total dose of R115777 for a shorter duration (EJ-1 and LX-1). Antitumor activity was associated with decreased cell proliferation (Ki-67), increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), and decreased angiogenesis. A reduction in tumor angiogenic cytokine levels (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) correlated with a reduction in tumor vascularity (CD31).
  
  
  CONCLUSIONS
  Overall, ABT-100 has an acceptable pharmacokinetic profile, is well tolerated, and possesses broad-spectrum antitumor activity against a series of xenograft models similar to farnesyltransferase inhibitors in clinical development; therefore, it is an attractive candidate for clinical evaluation.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Ferguson
authors.forename: Luis E
authors.initials: LE
authors.lastname: Rodriguez
authors.forename: Joann P
authors.initials: JP
authors.lastname: Palma
authors.forename: Marion
authors.initials: M
authors.lastname: Refici
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jarvis
authors.forename: Jacqueline
authors.initials: J
authors.lastname: O'Connor
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Sullivan
authors.forename: David
authors.initials: D
authors.lastname: Frost
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Joy
authors.initials: J
authors.lastname: Bauch
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
authors.forename: Saul
authors.initials: S
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Ingrid B J K
authors.initials: IB
authors.lastname: Joseph
mesh_terms: D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019540:Area Under Curve; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D051231:Farnesyltranstransferase; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: C503142:ABT-100; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase