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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 plateletderived growth factor (PDGF) receptor families (e.g., KDR IC 50 = 4 nmol/L) but has much less activity (IC 50 s > 1 Mmol/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-B, 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 Mg/mL, z7 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]

Background: NH125 inhibits cancer cell growth through inhibition of eukaryotic elongation factor-2 kinase (eEF2K). Results: NH125 induces eEF2 phosphorylation (peEF2) through multiple pathways in cancer cells. Conclusion: NH125 is not an eEF2K inhibitor in cancer cells. Inhibition of cell growth correlates with induction of peEF2. Significance: NH125-induced peEF2 corrects a misconception and provides an opportunity for a new multipathway approach to anticancer therapies.

These experiments provide an explanation for the observation that two intravenous injections of lipopolysaccharide (LPS) spaced 5 h apart in rabbits cause tumor necrosis factor/cachectin (TNF) levels to rise in the blood only after the first LPS injection. Herein we show that treatment of elicited peritoneal exudate rabbit macrophages (PEM) with two doses of LPS given 9 h apart results in a marked reduction in TNF production by the second LPS exposure. This state of hyporesponsiveness is a result of adaptation to LPS, is induced by LPS concentrations that are 1,000-fold less than required to induce TNF production (picograms vs. nanograms), is characterized by a decrease in LPS-induced TNF mRNA without any change in TNF mRNA half-life, is not changed by including indomethacin in cultures, and is specific for LPS since LPSadapted cells display a TNF response to heat-killed Staphylococcus aureus that is at least as good as that observed in control

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