Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions.
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.
Division of Biology, Eisai Inc., Andover, Massachusetts, USA.
Murray J
MJ
Towle
Kathleen A
KA
Salvato
Bruce F
BF
Wels
Kimberley K
KK
Aalfs
Wanjun
W
Zheng
Boris M
BM
Seletsky
Xiaojie
X
Zhu
Bryan M
BM
Lewis
Yoshito
Y
Kishi
Melvin J
MJ
Yu
Bruce A
BA
Littlefield
D050256:Antimitotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005663:Furans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018922:HL-60 Cells; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D007659:Ketones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014316:Tritium; D020298:U937 Cells; D000095662:Polyether Polyketides
D050256:Antimitotic Agents; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; D007659:Ketones; D019253:Proto-Oncogene Proteins c-bcl-2; D014316:Tritium; C421616:ER 076349; C490954:eribulin; D000095662:Polyether Polyketides