PMID: 20650059Feb 1, 1995Paper

Differential toxicities of cyclophosphamide and its glutathione metabolites to A549 cells

Toxicology in Vitro : an International Journal Published in Association with BIBRA
C S PerryJ P Kehrer

Abstract

Cyclophosphamide (CP), a widely used antineoplastic agent, is metabolized to species responsible for both the therapeutic and toxic effects of this drug. Acrolein is believed to be the primary toxic metabolite. This alpha,beta-unsaturated aldehyde reacts rapidly with glutathione (GSH) and can then be further metabolized to the mercapturic acid derivatives. The toxicities of the acrolein-glutathione adduct, 3-oxopropyl glutathione (oxoPrGSH) and the acrolein mercapturic acid derivatives S-3 oxopropyl N-acetylcysteine (oxoPrMCA) and S-3 hydroxypropyl N-acetylcysteine (hydroxyPrMCA) have not been fully tested. OxoPrMCA, hydroxyPrMCA and oxoPrGSH were synthesized. The toxicities of these compounds, along with those of CP and acrolein, were assessed by measuring their effects on the growth of human type II A549 lung carcinoma cells using the alamarBlue assay. Each compound was incubated with A549 cells under serum-free conditions for 2 hr, followed by 94 hr more growth in the presence of fresh medium with serum. A 50% reduction in cell growth 72 hr after treatment was achieved with 83 muM oxoPrMCA or 4 muM acrolein. No significant toxicity was seen with hydroxyPrMCA (10 mM) or oxoPrGSH (5 mm). CP (5 mM) also had no effect on the gro...Continue Reading

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