Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.
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.
Ferguson
Debra
D
Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Rodriguez
Luis E
LE
Palma
Joann P
JP
Refici
Marion
M
Jarvis
Kenneth
K
O'Connor
Jacqueline
J
Sullivan
Gerard M
GM
Frost
David
D
Marsh
Kennan
K
Bauch
Joy
J
Zhang
Haiying
H
Lin
Nan-Horng
NH
Rosenberg
Saul
S
Sham
Hing L
HL
Joseph
Ingrid B J K
IB
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*
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