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Cancer Chemother Pharmacol. 2016 Apr;77(4):777-85. doi: 10.1007/s00280-016-2995-9. Epub 2016 Feb 25.

Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity.

Author information

1
Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.
2
Cardiology Department, University Hospital, Dijon, France.
3
Pharmacology Group, Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 33 El Bohouth St., Dokki, P.O. 12622, Giza, Egypt.
4
Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France. cvergely@u-bourgogne.fr.

Abstract

PURPOSE:

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 cardiotoxicity, 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 intra-peritoneal injection of either saline, DOX (6 mg/kg), TRZ (10 mg/kg) or both (DOX-TRZ). Transthoracic echocardiography was performed 24 h 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. 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, whereas the expression of 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.

KEYWORDS:

Cardiotoxicity; Doxorubicin; Overweight; Postnatal programming; Trastuzumab

PMID:
26914236
DOI:
10.1007/s00280-016-2995-9
[Indexed for MEDLINE]

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