In prior studies, it was demonstrated that the redox metabolism of
doxorubicin leads to the formation of promutagenic oxidized
DNA bases in human
chromatin, suggesting a potential mechanism for
doxorubicin-related
second malignancies. To determine whether a similar type of DNA damage is produced in the clinic, peripheral blood mononuclear cell
DNA from 15 women treated with infusional
doxorubicin (165 mg/m(2)) as a single agent was examined for 14 modified bases by gas chromatography/mass spectrometry with selected ion monitoring. Prior to the 96-hour
doxorubicin infusion, 13 different oxidized bases were present in all
DNA samples examined.
Chemotherapy, producing a steady-state level of 0.1 microM
doxorubicin, increased
DNA base oxidation up to 4-fold compared to baseline values for 9 of the 13 bases studied. Maximal base oxidation was observed 72 to 96 hours after
doxorubicin treatment was begun; the greatest significant increases were found for Thy Gly (4.2-fold), 5-OH-Hyd (2.5-fold),
FapyAde (2.4-fold), and 5-OH-MeUra (2.4-fold). The level of the promutagenic base
FapyGua increased 1.6-fold (P < .02), whereas no change in 8-OH-Gua levels was observed in peripheral blood mononuclear cell
DNA during the
doxorubicin infusion. These results suggest that
DNA base damage similar to that produced by ionizing radiation occurs under clinical conditions in hematopoietic cells after
doxorubicin exposure. If
doxorubicin-induced
DNA base oxidation occurs in primitive hematopoietic precursors, these lesions could contribute to the mutagenic or toxic effects of the
anthracyclines on the bone marrow.