6533b862fe1ef96bd12c76e0

RESEARCH PRODUCT

0004 : Overweight in mice induced by perinatal programming exacerbates doxorubicin and trastuzumab cardiotoxicity

subject

description

Background Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardio \toxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ. Methods Immediately after birth, litters of C57BL/6 mice were either maintained at 9 pups (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce programming of ~15% overweight through postnatal overfeeding. At 4 months, NL and SL mice received a single intraperitoneal injection of either saline, DOX (6 mg/kg), or TRZ (10 mg/kg) or both (DOX-TRZ). Transthoracic echocardiography was performed 24 hours before as well as 10 and 20 days after treatments. Results Twenty days after DOX administration, systolic dysfunction was observed only in the overweight SL group, while NL mice group had a normal left ventricular ejection fraction (LVEF). However, in the NL group, functional impairment appeared when TRZ was co-administered. Forty-eight hours after drug administration, gene expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX-TRZ mice of both the NL and SL group, wher β-MHC increased significantly in overweight-SL mice only. Conclusions In an acute model of DOX cardiotoxicity, moderately overweight adult mice were more sensitive to cardiac systolic impairment. Moreover, our results confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in lean mice. The author hereby declares no conflict of interest