Oxidative DNA base modifications in peripheral blood mononuclear cells of patients treated with high-dose infusional doxorubicin

In prior studies, it was demonstrated that the redox metabolism of doxorubi cin leads to the formation of promutagenic oxidized DNA bases in human chro matin, suggesting a potential mechanism for doxorubicin-related second mali gnancies. To determine whether a similar type of DNA damage is produced in the clinic, peripheral blood mononuclear cell DNA from 15 women treated wit h infusional doxorubicin (165 mg/m(2)) as a single agent was examined for 1 4 modified bases by gas chromatography/mass spectrometry with selected ion monitoring. Prior to the 96-hour doxorubicin infusion, 13 different oxidize d bases were present in all DNA samples examined. Chemotherapy, producing a steady-state level of 0.1 muM doxorubicin, increased DNA base oxidation up to 4-fold compared to baseline values for 9 of the 13 bases studied. Maxim al base oxidation was observed 72 to 96 hours after doxorubicin treatment w as begun; the greatest significant increases were found for Thy Gly (4,2-fo ld), 8-OH-Hyd (2.5-fold), FapyAde (2.4-fold), and B-OH-MeUra (2.4-fold). Th e level of the promutagenic base FapyGua increased 1.6-fold (P < .02), wher eas no change in 8-OH-Gua levels was observed in peripheral blood mononucle ar cell DNA during the doxorubicin infusion. These results suggest that DNA base damage similar to that produced by ionizing radiation occurs under cl inical conditions in hematopoietic cells after doxorubicin exposure. If dox orubicin-induced DNA base oxidation occurs in primitive hematopoietic precu rsors, these lesions could contribute to the mutagenic or toxic effects of the anthracyclines on the bone marrow. (Blood.2001;97:2839-2845) (C) 2001 b y The American Society of Hematology.