This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Albert, D. H. Articles by Davidsen, S. K. Search for Related Content PubMed PubMed Citation Articles by Albert, D. H. Articles by Davidsen, S. K.

Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Daniel H. Albert, Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47J, Building AP9/2, 100 Abbott Park Road, Abbott Park, IL 60064-3500. Phone: 847-937-3844; Fax: 847-935-3622. E-mail: daniel.h.albert{at}abbott.com

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC₅₀ = 4 nmol/L) but has much less activity (IC₅₀s > 1 µmol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC₅₀ = 2, 4, and 7 nmol/L for PDGFR-ß, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC₅₀ = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED₅₀ = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED₅₀ = 1.5–5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC₅₀ corrected for plasma protein binding = 0.08 µg/mL, 7 hours) than with plasma area under the curve or C_max. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer. [Mol Cancer Ther 2006;5(4):995–1006]

¹ J. Li et al. ABT-869 a multi-targeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Cancer Res, submitted for publication.

Received 10/ 7/05; revised 1/30/06; accepted 2/21/06.

This article has been cited by other articles:

				J. G. Conway, H. Pink, M. L. Bergquist, B. Han, S. Depee, S. Tadepalli, P. Lin, R. C. Crumrine, J. Binz, R. L. Clark, et al. Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 41 - 50. [Abstract] [Full Text] [PDF]

				J. N. Contessa, M. S. Bhojani, H. H. Freeze, A. Rehemtulla, and T. S. Lawrence Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells Cancer Res., May 15, 2008; 68(10): 3803 - 3809. [Abstract] [Full Text] [PDF]

				L. Li, X. Lin, A. R. Shoemaker, D. H. Albert, S. W. Fesik, and Y. Shen Hypoxia-Inducible Factor-1 Inhibition in Combination with Temozolomide Treatment Exhibits Robust Antitumor Efficacy In vivo Clin. Cancer Res., August 1, 2006; 12(15): 4747 - 4754. [Abstract] [Full Text] [PDF]

				J. Guo, P. A. Marcotte, J. O. McCall, Y. Dai, L. J. Pease, M. R. Michaelides, S. K. Davidsen, and K. B. Glaser Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol. Cancer Ther., April 1, 2006; 5(4): 1007 - 1013. [Abstract] [Full Text] [PDF]