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 [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.
Subject(s)
Antimitotic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Furans/pharmacology , Ketones/pharmacology , Mitosis/drug effects , Antimitotic Agents/administration & dosage , Drug Administration Schedule , Drug Interactions , Furans/administration & dosage , Furans/pharmacokinetics , HL-60 Cells , HeLa Cells , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Jurkat Cells , Ketones/administration & dosage , Ketones/pharmacokinetics , Phosphorylation/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Tritium , U937 CellsABSTRACT
A structurally simplified macrolactone analogue of halichondrin B was identified that retains the potent cell growth inhibitory activity of the natural product in vitro.
Subject(s)
Ethers, Cyclic/chemistry , Ethers, Cyclic/pharmacology , Lactones/chemistry , Lactones/pharmacology , Animals , Cell Division/drug effects , Cell Line, Tumor , Ethers, Cyclic/chemical synthesis , Humans , Lactones/chemical synthesis , Macrolides , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.
