Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type-specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [ Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions. Cancer Res; 71(2); 496-505. Ó2011 AACR.

No abstract

No abstract

No abstract

SummaryScu-PA was cleaved by thrombin after arginine-156 to yield a two-chain molecule with low amidolytic activity and resistance to cleavage by plasmin. 125I-fibrin-labeled clots were dissolved in vitro by thrombin-cut scu-PA, but only at concentrations 10- to 50-fold greater than that needed for scu-PA. Three hours of incubation produced 100, 80, and 31% lysis with 100, 50, and 25 pg/ml thrombin-cut scu-PA. Thrombin-cut scu-PA, scu-PA, and tcu-PA yielded linear dose responses in the rabbit jugular venous thrombosis model. The dose required to reach 40% lysis was 2 mg/kg for scu-PA, 3 mg/kg for tcu-PA, and 4 mg/kg for thrombin-cut scu-PA. No significant consumption of fibrinogen or alpha2-antiplasmin levels was observed with thrombin-cut scu-PA while the level of fibrinogen and alpha2-antiplasmin decreased to about 50 and 40%, respectively, with scu-PA and to less than 10% of baseline with tcu-PA. Thus, while less potent than scu-PA, thrombin-cut scu-PA appears to be a more fibrin-specific thrombolytic agent than scu-PA.