Reducing undesirable hepatic clearance of a tumor-targeted vinca alkaloid via novel saccharopeptidic modifications

During a phase I trial of EC145 (a folate-targeted vinca alkaloid conjugate), constipation was identified as the dose-limiting toxicity, probably from a nonfolate receptor-related liver clearance process capable of releasing unconjugated vinca alkaloid from EC145 and shuttling it to the bile. Here,...

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Published in:The Journal of pharmacology and experimental therapeutics 2011-02, Vol.336 (2), p.336-343
Main Authors: Leamon, Christopher P, Reddy, Joseph A, Klein, Patrick J, Vlahov, Iontcho R, Dorton, Ryan, Bloomfield, Alicia, Nelson, Melissa, Westrick, Elaine, Parker, Nikki, Bruna, Kristen, Vetzel, Marilynn, Gehrke, Mark, Nicoson, Jeffrey S, Messmann, Richard A, LoRusso, Patricia M, Sausville, Edward A
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - toxicity
Dose-Response Relationship, Drug
Drug Discovery
Female
Folate Receptors, GPI-Anchored - physiology
Folic Acid - analogs & derivatives
Folic Acid - pharmacokinetics
Folic Acid - toxicity
Kidney - metabolism
Liver - metabolism
Male
Metabolic Clearance Rate
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Vinca Alkaloids - pharmacokinetics
Vinca Alkaloids - toxicity
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Summary:During a phase I trial of EC145 (a folate-targeted vinca alkaloid conjugate), constipation was identified as the dose-limiting toxicity, probably from a nonfolate receptor-related liver clearance process capable of releasing unconjugated vinca alkaloid from EC145 and shuttling it to the bile. Here, we report on the selective placement of novel carbohydrate segments (1-amino-1-deoxy-glucitolyl-γ-glutamate) spaced in-between the folate and vinca alkaloid moieties of EC145, which yielded a new agent (EC0489) that is equipotent but less toxic than EC145. Whereas both compounds could cure tumor-bearing mice reproducibly, EC0489 differed from EC145 with i) a shorter elimination half-life, ii) approximately 70% decrease in bile clearance, iii) a 4-fold increase in urinary excretion, and iv) improved tolerability in rodents. This combination of improvements justified the clinical evaluation of EC0489 where currently administered dose levels have exceeded the maximal tolerated dose of EC145 by approximately 70%, thereby reflecting the translational benefits to this new approach.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.110.175109