The antiproliferative and immunotoxic effects of L-canavanine and L-canaline

Aimee K. Bence, David R. Worthen, Val R. Adams, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

L-Canavanine and its arginase-catalyzed metabolite, L-canaline, are two novel anticancer agents in development. Since the immunotoxic evaluation of agents in development is a critical component of the drug development process, the antiproliferative effects of L-canavanine and L-canaline were evaluated in vitro. Both L-canavanine and L-canaline were cytotoxic to peripheral blood mononucleocytes (PBMCs) in culture. Additionally, the mononucleocytes were concurrently exposed to either L-canavanine or L-canaline and each one of a series of compounds that may act as metabolic inhibitors of the action of L-canavanine and L-canaline (L-arginine, L-ornithine, D-arginine, L-lysine, L-homoarginine, putrescine, L-ω-nitro arginine methyl ester and L-citrulline). The capacity of these compounds to overcome the cytotoxic effects of L-canavanine or L-canaline was assessed in order to provide insight into the biochemical mechanisms that may underlie the toxicity of these two novel anticancer agents. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. The elucidation of the biochemical mechanisms associated with the effects of L-canavanine and L-canaline on lymphoproliferation may be useful for maximizing the therapeutic effectiveness and minimizing the toxicity of these novel anticancer agents.

Original languageEnglish
Pages (from-to)313-320
Number of pages8
JournalAnti-Cancer Drugs
Volume13
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Amino acid metabolism
  • Immunotoxicity
  • L-canaline
  • L-canavanine

ASJC Scopus subject areas

  • Medicine (all)

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