title: Leukocyte 8-oxo-7,8-dihydro-2'-deoxyguanosine and comet assay in epirubicin-treated patients.
abstract: Epirubicin fights cancer through topoisomerase II inhibition, hence producing DNA strand breaks that finally lead to cell apoptosis. But anthracyclines produce free radicals that may explain their adverse effects. Dexrazoxane--an iron chelator--was proven to decrease free radical production and anthracycline cardiotoxicity. In this article, we report the concentrations of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) relative to 2'-deoxyguanosine (dGuo), and comet assay results from a study including 20 cancer patients treated with epirubicin. Plasma concentrations of vitamins A, E, C and carotenoids are also reported. All data were obtained before and immediately after epirubicin infusion. The ratios of 8-Oxo-dGuo to dGuo were measured in leukocyte DNA by HPLC-coulometry after NaI extraction of nucleic acids. Vitamins A and E and carotenoids were measured by HPLC-spectrophotometry. Vitamin C was measured by HPLC-spectrofluorimetry. Median 8-oxo-dGuo/dGuo ratios increased significantly from 0.34 to 0.48 lesions per 100,000 bases while per cent of tail DNA increased from 3.47 to 3.94 after chemotherapy 8-Oxo-dGuo/dGuo and per cent of tail DNA medians remained in the normal range. Only vitamin C decreased significantly from 55.4 to 50.3 microM Decreases in vitamins A, E, lutein and zeaxanthin were not significant, but concentrations were below the lower limit of the normal range both before and after chemotherapy. Only the correlation between comet assay results and vitamin C concentrations was significant (rho =-0.517, p = 0.023). This study shows that cellular DNA is damaged by epirubicin-generated free radicals which produce the mutagenic modified base 8-oxo-dGuo and are responsible for strand breaks. However, strand breaks are created not only by free radicals but also by topoisomerase II inhibition. In a previous study we did not find any significant change in urinary 8-oxo-dGuo excretion after adriamycin treatment. However, 8-oxo-dGuo may have increased at the end of urine collection as DNA repair and subsequent kidney elimination are relatively slow processes. In another study, authors used GC-MS to detect 8-oxo-dGuo in DNA and did not find any change after prolonged adriamycin infusion. Reasons for these apparent discrepancies are discussed.
authors.affiliation: Department of Cancerology, University Hospital, Grenoble, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Mousseau
authors.forename: Henri
authors.initials: H
authors.lastname: Faure
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hininger
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bayet-Robert
authors.forename: Alain
authors.initials: A
authors.lastname: Favier
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D020552:Comet Assay; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D015251:Epirubicin / Q000627:therapeutic use*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D014801:Vitamin A / Q000097:blood; D014810:Vitamin E / Q000097:blood
chemical_list: D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D014801:Vitamin A; D014810:Vitamin E; D015251:Epirubicin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D001205:Ascorbic Acid