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Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor

2006; American Association for Cancer Research; Volume: 5; Issue: 4 Linguagem: Inglês

10.1158/1535-7163.mct-05-0410

1538-8514

Daniel H. Albert, Paul Tapang, Terrance J. Magoc, Lori J. Pease, David R. Reuter, Ru-Qi Wei, Junling Li, Jun Guo, Peter F. Bousquet, Nayereh Ghoreishi‐Haack, Baole Wang, Gail Bukofzer, Yichun Wang, Jason Stavropoulos, Kresna Hartandi, Amanda Niquette, Nirupama B. Soni, Eric F. Johnson, Jennifer McCall, Jennifer J. Bouska, Yanping Luo, Cherrie K. Donawho, Yujia Dai, Patrick A. Marcotte, Keith B. Glaser, Michael R. Michaelides, Steven K. Davidsen,

HER2/EGFR in Cancer Research

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 micromol/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-beta, 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 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.