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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-01, Vol.71 (2), p.496-505
• Main Authors: TOWLE, Murray J, SALVATO, Kathleen A, LITTLEFIELD, Bruce A, WELS, Bruce F, AALFS, Kimberley K, WANJUN ZHENG, SELETSKY, Boris M, XIAOJIE ZHU, LEWIS, Bryan M, KISHI, Yoshito, YU, Melvin J
• Format: Article
• Language: English
• Subjects: Antimitotic Agents - administration & dosage; Antimitotic Agents - pharmacology; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Drug Administration Schedule; Drug Interactions; Furans - administration & dosage; Furans - pharmacokinetics; Furans - pharmacology; HeLa Cells; Heterocyclic Compounds, 4 or More Rings - administration & dosage; Heterocyclic Compounds, 4 or More Rings - pharmacokinetics; Heterocyclic Compounds, 4 or More Rings - pharmacology; HL-60 Cells; Humans; Jurkat Cells; Ketones - administration & dosage; Ketones - pharmacokinetics; Ketones - pharmacology; Medical sciences; Mitosis - drug effects; Pharmacology. Drug treatments; Phosphorylation - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tritium; Tumors; U937 Cells
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-1874

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 [3H]eribulin accumulates to lower intracellular levels than [3H]ER-076349, yet is retained longer and at higher levels. Similar findings occurred with irreversible vincristine and reversible vinblastine, pointing to persistent cellular retention as a component of irreversibility. 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.