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

被引:183
作者
Albert, DH [1 ]
Tapang, P [1 ]
Magoc, TJ [1 ]
Pease, LJ [1 ]
Reuter, DR [1 ]
Wei, RQ [1 ]
Li, JL [1 ]
Guo, J [1 ]
Bousquet, PF [1 ]
Ghoreishi-Haack, NS [1 ]
Wang, B [1 ]
Bukofzer, GT [1 ]
Wang, YC [1 ]
Stavropoulos, JA [1 ]
Hartandi, K [1 ]
Niquette, AL [1 ]
Soni, N [1 ]
Johnson, EF [1 ]
McCall, JO [1 ]
Bouska, JJ [1 ]
Luo, Y [1 ]
Donawho, CK [1 ]
Dai, YJ [1 ]
Marcotte, PA [1 ]
Glaser, KB [1 ]
Michaelides, MR [1 ]
Davidsen, SK [1 ]
机构
[1] Canc Res, Global Pharmaceut Res & Dev, Abbott Labs, Abbott Pk, IL 60064 USA
关键词
cancer research; Global Pharmaceutical Research and Development; Abbott laboratories; Abbott park; Illinois;
D O I
10.1158/1535-7163.MCT-05-0410
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (IC(50)s > 1 mu mol/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 mu g/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.
引用
收藏
页码:995 / 1006
页数:12
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