Doxorubicin Cardiotoxicity in Young Tumor‐Bearing Mice

Abstract

BackgroundChildhood cancer survivors have about 15‐times higher risk of heart failure than their siblings mainly due to the cardiotoxicity of chemotherapy. Nearly 50% of pediatric cancer patients receive doxorubicin (DOX) which is known to be cardiotoxic. DOX‐induced cardiotoxicity had been extensively studied in tumor‐free mouse models. The objective of the current study is to characterize a juvenile tumor‐bearing immunocompetent mouse model of DOX‐induced cardiotoxicity.MethodsJuvenile five‐week old male C57Bl/6 mice were injected subcutaneously with EL4 lymphoma cells (5X104 cells/mouse) in the flank region suspended in sterile PBS, while tumorfree mice were only injected with sterile PBS. One week after tumor implantation, both tumorfree and tumor‐bearing mice were injected intraperitoneally with either a clinically relevant dose of DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, mice were euthanized and the hearts and tumors were harvested and weighed. Gene expression of molecular markers of cardiotoxicity and inflammation was quantified using real‐time PCR.ResultsDOX 4 mg/kg/week for 3 weeks significantly reduced tumor weights in EL4 tumor‐bearing mice. DOX administration caused significant cardiac atrophy in tumor‐free and tumor‐bearing mice. Moreover, tumor itself caused a significant reduction in heart weight compared to tumor‐free mice. Additionally, DOX administration induced the expression of markers of cardiotoxicity, ANP and BNP, in both tumor‐free and tumor‐bearing mice. Saline‐treated tumor‐bearing mice demonstrated higher expression of TNF‐alpha, an inflammatory marker, compared to tumor‐free mice.ConclusionWe have established a juvenile tumor‐bearing immunocompetent mouse model to investigate DOX‐induced cardiotoxicity. Our tumor‐bearing mouse model will optimize our understanding of the interplay between tumor and DOX‐induced cardiotoxicity. Additionally, this clinically relevant model will be used for investigation of cardioprotective strategies that mitigate DOX cardiotoxicity without compromising its chemotherapeutic efficacy before translating to the clinical settings.Support or Funding InformationResearch was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494, and by a grant from the St. Baldrick’s Foundation [B.N.Z.]. B.N.Z. is a Masonic Cancer Center Women’s Health Scholar, sponsored by the Masonic Cancer Center, and administered by the University of Minnesota Women’s Health Research Program.