1. Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.
- Author
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Ferguson D, Rodriguez LE, Palma JP, Refici M, Jarvis K, O'Connor J, Sullivan GM, Frost D, Marsh K, Bauch J, Zhang H, Lin NH, Rosenberg S, Sham HL, and Joseph IB
- Subjects
- Administration, Oral, Angiogenesis Inhibitors pharmacokinetics, Animals, Antineoplastic Agents blood, Antineoplastic Agents pharmacokinetics, Area Under Curve, 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, Humans, Imidazoles blood, Imidazoles pharmacokinetics, Interleukin-8 metabolism, Male, Mice, Mice, Nude, Mice, SCID, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Neovascularization, Pathologic prevention & control, Vascular Endothelial Growth Factor A metabolism, Alkyl and Aryl Transferases antagonists & inhibitors, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Apoptosis drug effects, Imidazoles pharmacology, Xenograft Model Antitumor Assays methods
- Abstract
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.
- Published
- 2005
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