[原著］A preliminary study on the effect of myeloperoxidase on etoposide-induced HPRT mutants in HL-60 cells

概要

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Topoisomerase II (Topo II) -directed antitumor drug, etoposide (VP-16) -related leukemia (T-cell acute myelogenous leukemia, t-AML) occurs in about 10% of drug-treated patients. Understanding the mechanisms underlying leukemia induced by VP-16 is important for the development of safer drugs against leukemia. It has been postulated that redox cycling of VP-16 initiated by myeloperoxidase (MPO) produces reactive oxygen species responsible for the genotoxicity of this agent in myeloid precursors, leading to chromosomal translocations responsible for t-AML. To test this hypothesis, MPO activity of HL-60 cells were down-regulated by treating the cells with succinyl acetone (SA). The genotoxicity of VP-16 in these cells was then determined by analyzing the frequencies of mutations in the hypoxanthine phosphoribosyl transferase (HPRT) gene and compared with that in cells without prior SA-treatment. The results showed that the VP-16-induced HPRT mutant frequency in cells whose MPO activity was inhibited by prior SA treatment was significantly decreased by 78.8%, as compared with cells without prior SA-treatment. These results support our hypothesis that VP-16 induces genotoxicity and carcinogenicity through MPOmediated oxidative activation of VP-16.
琉球医学会の論文
2004-00-00