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

J Pharmacol Exp Ther. 2011 Feb;336(2):336-43. doi: 10.1124/jpet.110.175109. Epub 2010 Oct 26.


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.

MeSH terms

  • 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


  • Antineoplastic Agents
  • EC 0489
  • EC145
  • Folate Receptors, GPI-Anchored
  • Vinca Alkaloids
  • Folic Acid