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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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

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 IC(50) = 4 nmol/L) but has much less activity (IC(50)s > 1 mumol/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 (IC(50) = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC(50) = 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 (ED(50) = 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 (ED(50) = 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 IC(50) corrected for plasma protein binding = 0.08 mug/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]


  1. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Albert, D.H., Tapang, P., Magoc, T.J., Pease, L.J., Reuter, D.R., Wei, R.Q., Li, J., Guo, J., Bousquet, P.F., Ghoreishi-Haack, N.S., Wang, B., Bukofzer, G.T., Wang, Y.C., Stavropoulos, J.A., Hartandi, K., Niquette, A.L., Soni, N., Johnson, E.F., McCall, J.O., Bouska, J.J., Luo, Y., Donawho, C.K., Dai, Y., Marcotte, P.A., Glaser, K.B., Michaelides, M.R., Davidsen, S.K. Mol. Cancer Ther. (2006) [Pubmed]
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