Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions
| Autor: | Xiaojie Zhu, Bruce F. Wels, Bruce A. Littlefield, Yoshito Kishi, Bryan M. Lewis, Boris M. Seletsky, Murray J. Towle, Wanjun Zheng, Melvin J. Yu, Kathleen A. Salvato, Kimberley K. Aalfs |
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| Rok vydání: | 2010 |
| Předmět: |
Eribulin Mesylate
Cancer Research Mitosis HL-60 Cells Pharmacology Biology Antimitotic Agents Tritium Heterocyclic Compounds 4 or More Rings Drug Administration Schedule chemistry.chemical_compound Jurkat Cells In vivo Antineoplastic Combined Chemotherapy Protocols medicine Humans Drug Interactions Viability assay Phosphorylation Furans U937 Cells Ketones Vinblastine Blockade Oncology chemistry Proto-Oncogene Proteins c-bcl-2 Antimitotic Agent medicine.drug Eribulin HeLa Cells |
| Zdroj: | Cancer research. 71(2) |
| ISSN: | 1538-7445 |
| Popis: | 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. Cancer Res; 71(2); 496–505. ©2011 AACR. |
| Databáze: | OpenAIRE |
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