Oxidative DNA Damage as an Integrative Marker of Redox Dysfunction Associated with Doxorubicin-Induced Cardiotoxicity...

Doxorubicin (Dox) is a cornerstone in the treatment of pediatric acute lymphoblastic leukemia (ALL), but its use is limited by dose-dependent cardiotoxicity. Oxidative stress, arising from mitochondrial dysfunction, enzymatic generation of reactive oxygen species, and cardiotoxic metabolites, has been implicated as a central mechanism, with interindividual variability partly influenced by genetic factors. This study evaluated oxidative DNA damage 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an integrative marker of redox-related pathways in Dox-induced cardiotoxicity. In a prospective case-control study, 93 pediatric patients with ALL treated with Dox and 63 controls were included. Cardiotoxicity was assessed by serial echocardiography, and 8-OHdG levels were measured by ELISA. Genotyping of ABCC1 rs3743527, NCF4 rs1883112, and CBR3 rs1056892 was performed, and multivariable analyses were conducted. Dox-treated patients showed higher 8-OHdG levels than controls, and patients with cardiotoxicity (n = 11) had higher levels than those without. A higher frequency and severity of cardiotoxicity was observed in female patients, although this finding should be interpreted cautiously. Although allele frequencies did not reach statistical significance, distinct distribution patterns were observed between groups. These findings suggest that 8-OHdG may function as an integrative marker of redox dysfunction associated with Dox-induced cardiotoxicity.