Abstract
BackgroundAnthracycline chemotherapy is an effective and widely used treatment for solid tumors and hematological malignancies regardless of its known cardiotoxicity. The mechanisms of the cardiotoxicity are not fully understood and methods to protect the heart during or following anthracycline chemotherapy are currently unclear. In order to examine the efficacy of human cell based therapy in anthracycline-induced injury, we characterized a mouse model using an immune compromised strain of mice capable of accepting human cells.MethodsImmune compromised mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) were repeatedly exposed to pharmaceutical grade doxorubicin (0.5 mg/kg – 4 mg/kg). Cardiotoxicity was assessed by echocardiography and μCT imaging of the coronary vascular bed as well as by flow cytometry and by histological assessments of anthracycline-induced cardiac tissue damage.ResultsThe immune compromised mice were highly susceptible to doxorubicin treatment. Doxorubicin induced both systemic and cardiac toxicities. Gastrointestinal and hepatic injury occurred at 4 mg/kg and 1.5 mg/kg dosing while mice receiving 0.5 mg/kg weekly only displayed hepatic damage. Repeated exposure to 0.5 mg/kg anthracyclines resulted in cardiac toxicity. Flow cytometric analysis of hearts indicated a loss in endothelial and cardiac progenitor cells after doxorubicin treatment. This endothelial loss is corroborated by the lack of small vessels detected by μCT in the hearts of mice exposed to doxorubicin. Histological assessment shows no overt cardiomyocyte injury but livers from mice treated with doxorubicin show marked hepatic plate atrophy with intracytoplasmic and canalicular cholestasis, rare pericentral hepatocellular necrosis and significant zone 3 iron accumulation, likely an indication of metabolic injury due to doxorubicin toxicity.ConclusionsImmune compromised mice are sensitive to doxorubicin therapy resulting in systemic complications in addition to cardiovascular toxicity. Anthracycline-induced cardiotoxicity is observed at very low doses in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice.
Highlights
Anthracycline chemotherapy is an effective and widely used treatment for solid tumors and hematological malignancies regardless of its known cardiotoxicity
In the days following the first round of chemotherapy, all doxorubicin mice began exhibiting signs of distress and rapid weight loss (Fig. 1a)
In study I via flow cytometry, we found no significant differences in CD45pos immune cells after 2 weeks of doxorubicin treatment but this may change if we looked at a later time point in the study after chemotherapy treatment is completed since the immune system can be altered
Summary
Anthracycline chemotherapy is an effective and widely used treatment for solid tumors and hematological malignancies regardless of its known cardiotoxicity. The mechanisms of the cardiotoxicity are not fully understood and methods to protect the heart during or following anthracycline chemotherapy are currently unclear. In order to examine the efficacy of human cell based therapy in anthracycline-induced injury, we characterized a mouse model using an immune compromised strain of mice capable of accepting human cells. There are over 15 million cancer survivors in the United States, which amounts to almost 5% of the country’s population [1]. Heart disease risk is increased in long-term cancer survivors treated with anthracyclines (i.e. Adriamycin known as doxorubicin, Idarubicin, or Daunorubicin), a class of anti-tumor antibiotics that intercalate into DNA to inhibit synthesis inducing DNA damage and halting cell proliferation [2]. It is difficult to identify a common mechanism of injury with the current published studies because the study design, dosing, length of treatment, severity of injury, and endpoints vary and make comparisons between studies difficult
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