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 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.
Doroshow
J H
JH
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Center, Duarte, CA 91010, USA. jdoroshow@coh.org
Synold
T W
TW
Somlo
G
G
Akman
S A
SA
Gajewski
E
E
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010084:Oxidation-Reduction
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004317:Doxorubicin