Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Abstract

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.

Cellular studies reveal mechanistic differences between taccalonolide A and paclitaxel

“…4-6). 20 Unfortunately, there is no clear indication to what extent cellular persistence is a desirable property for a drug. The relative reversibility of a compound does not often factor into cellular assays where the cells are constantly bathed in drug-containing media.…”

“…Clinically used drugs, including vincristine and eribulin, demonstrate a high degree of cellular persistence. 20 In contrast, the cellular effects of both paclitaxel and vinblastine, which are also clinically valuable microtubule targeting agents, are less persistent. 20 Further analysis of the relationship between in vitro reversibility and clinical efficacy may be valuable to identify whether there is a link between these factors.…”

6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells

“…Gajate and colleagues (48) reported that cells treated with the bicyclic colchicine analogue MCT for a short period of time (before induction of the apoptotic response) resumed proliferating; however, once the treatment period exceeded the tolerable threshold (cell line specific) and apoptosis was triggered, the cell proliferation capacity could not be restored by the removal of the inhibitor. Furthermore, Towle and colleagues showed that after 12 hours of treatment of U-937 cells (histiocytic lymphoma) with microtubule-targeting agents at concentrations that induced complete mitotic block, and 10 hours of washout, the mitotic arrest was reversible or irreversible depending on the compound (38). Small changes in chemical structures between analogues (e.g., eribulin vs. ER-076349, vincristine vs. vinblastine, colchicine vs. colcemid) led to profound differences in mitotic block reversibility.…”

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

“…A clonogenic assay was used to evaluate the ability of polygamain to inhibit colony formation of PC-3 cells after a 12-h exposure to the IC 50 concentration. Notable differences in cellular persistence have recently been noted among compounds representing diverse classes of microtubule-disrupting agents Towle et al, 2011). The effects of polygamain in this assay were compared with the effects of podophyllotoxin and CA-4.…”