Antitumor Activity of Orally Bioavailable Farnesyltransferase Inhibitor, ABT-100, Is Mediated by Antiproliferative, Proapoptotic, and Antiangiogenic Effects in Xenograft Models

• Published in: Clinical cancer research 2005-04, Vol.11 (8), p.3045-3054
• Main Authors: Ferguson, Debra, Rodriguez, Luis E, Palma, Joann P, Refici, Marion, Jarvis, Kenneth, O'Connor, Jacqueline, Sullivan, Gerard M, Frost, David, Marsh, Kennan, Bauch, Joy, Zhang, Haiying, Lin, Nan-Horng, Rosenberg, Saul, Sham, Hing L, Joseph, Ingrid B J K
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alkyl and Aryl Transferases - antagonists & inhibitors; angiogenesis; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Area Under Curve; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Farnesyltranstransferase; Fibroblast Growth Factor 2 - metabolism; FTI; Humans; Imidazoles - blood; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Interleukin-8 - metabolism; Male; Medical sciences; Mice; Mice, Nude; Mice, SCID; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Pharmacology. Drug treatments; proliferation; Vascular Endothelial Growth Factor A - metabolism; xenograft; Xenograft Model Antitumor Assays - methods
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-2041

Purpose: To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100. Experimental Design: 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.