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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2839-2845
NEOPLASIA
Oxidative DNA base modifications in peripheral blood mononuclear
cells of patients treated with high-dose infusional
doxorubicin
James H. Doroshow,
Timothy
W. Synold,
George Somlo,
Steven A. Akman, and
Ewa Gajewski
From the Department of Medical Oncology and
Therapeutics Research, City of Hope Comprehensive Center, Duarte,
CA, and Department of Cancer Biology, Comprehensive Cancer Center of
Wake Forest University, Winston-Salem, NC.
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/m2) 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 µM 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.
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