Possible Interaction: Glutathione and Perfosfamide

“Evidence was obtained showing that GSH protects against the cytotoxicity of 4-hydroperoxycyclophosphamide (4-OOH-CP) by minimizing the spontaneous fission of 4-hydroxycyclophosphamide (4-OH-CP), its breakdown product, to the ultimate toxic species, phosphoramide mustard (PM).”

“Exposure of K-562 cells to 4-HC resulted in a concentration- and time-dependent depletion of cellular GSH.”

“In conclusion, the data …, indicating that (a) 4-HC … GSH levels, (b) the lowering of cellular GSH levels enhances the toxicity of cisplatin, and (c) intact GSH stores are required … postulate that the cytotoxic synergism between 4-HC and cisplatin is modulated by GSH levels in this cell line.”

“To explain the sequence-dependent in vitro cytotoxic synergism between 4-hydroperoxycyclophosphamide (4-… cisplatin in the K-562 human leukemia cell line, we have hypothesized that 4-HC decreases … ( GSH ) levels and that the resulting diminution of the cellular protective … of GSH leads to the increased cytotoxicity of cisplatin.”

“In addition, it established that GSH acts as a competitive protecting agent against the in vitro toxicity of 4-HC in the K-562 cell line.”

“ 4-HC produced a marked reduction in GSH levels in NBMMC as well as AML blasts.”

“Subsequent treatment with 10 microM 4-hydroperoxycyclophosphamide 4-HC ), a self-activating derivative of cyclophosphamide, reduced the level of glutathione to less than 20% of control values.”

“These findings demonstrate that BHCNU potentiates the cytotoxicity of 4-HC and suggest that this is due to the increased formation of DNA interstrand cross-links caused by a reduced intracellular conjugation of 4-HC with glutathione which results in an increased binding of 4-HC to DNA targets.”