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.
Subject(s)
Ethers, Cyclic/chemistry , Ethers, Cyclic/pharmacology , Ketones/chemistry , Ketones/pharmacology , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Animals , Cell Division/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Ethers, Cyclic/chemical synthesis , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , Humans , Ketones/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrolides , Mice , Molecular Conformation , Structure-Activity RelationshipABSTRACT
A series of compounds possessing both H(1) histamine receptor antagonist and 5-lipoxygenase (5-LO) inhibitory activities was synthesized. The H(1)-binding scaffolds of cetirizine, efletirizine, and loratadine were linked to a lipophilic N-hydroxyurea, the 5-LO inhibiting moiety of zileuton. Both activities were observed in vivo, as was increased CYP3A4 inhibition compared to their respective single-function drugs. Selected analogs in the series were shown to be orally active in guinea pig models.
Subject(s)
Cetirizine/chemistry , Histamine H1 Antagonists/pharmacokinetics , Lipoxygenase Inhibitors , Loratadine/chemistry , Animals , Cetirizine/pharmacokinetics , Guinea Pigs , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/chemistry , Loratadine/pharmacokinetics , Models, Animal , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A series of novel compounds with both 5-lipoxygenase (5-LO) inhibitory and histamine H(1) receptor antagonist activity were designed for the treatment of asthma. These dual-function compounds were made by connecting 5-LO and H(1) pharmacophores,N-hydroxyureas and benzhydryl piperazines, respectively. A range of in vitro activities was observed, with the furan analog 10 demonstrating both activities in an animal model. The activities observed were compared to single-function drugs.
