Daunorubicin, a clinically useful
antitumor agent, induces mammary
adenocarcinoma in Sprague-Dawley rats. As part of an investigation of the mechanism of
tumor induction by
daunorubicin, the formation of
daunorubicin-DNA adducts has been investigated by 32P-postlabeling assay. Rat-liver
DNA incubated with either 0.05 or 0.1 mM
daunorubicin, rat-liver microsomes, and 5 mM reduced
nicotinamide adenine dinucleotide phosphate (
NADPH) for 1 h contained covalent
DNA adducts in addition to the endogenous adduct profile present in control
DNA. With 1.5 mM
cumene hydroperoxide serving as a cofactor, higher levels of these two adducts and two additional adducts were formed, all of which most likely were
daunorubicin-DNA adducts. This latter treatment also resulted in an intensification of three endogenous
DNA modifications over levels occurring in control
DNA. Covalent
DNA alterations in vivo were studied in rats treated with 20 mg/kg
daunorubicin for 2 days and 200 mg/kg on the 3rd day.
Daunorubicin-DNA adducts as observed in vitro could not be detected in
DNA of liver or mammary epithelial cells. The levels of endogenous modifications in
drug-treated rats were increased by 200% in mammary
DNA and by 50% in hepatic
DNA as compared with controls. It was concluded from these experiments that
daunorubicin may be metabolically activated to a reactive metabolite that binds covalently to
DNA. These
daunorubicin-DNA adducts may not play a role in
tumor induction because they were not detectable in vivo. However, the increase in levels of endogenous
DNA modifications induced by
daunorubicin both in vitro and in vivo is consistent with a role of this class of
DNA modification in the carcinogenic process.