Abstract
Doxorubicin (DOX) is one of the most widely used chemo-therapeutic agents in pediatric oncology. DOX elicits an inflammatory response in multiple organs, which contributes to DOX-induced adverse effects. Cancer itself causes inflammation leading to multiple pathologic conditions. The current study investigated the inflammatory response to DOX and tumors using an EL4-lymphoma, immunocompetent, juvenile mouse model. Four-week old male C57BL/6N mice were injected subcutaneously with EL4 lymphoma cells (5 × 104 cells/mouse) in the flank region, while tumor-free mice were injected with vehicle. Three days following tumor implantation, both tumor-free and tumor-bearing mice were injected intraperitoneally with either DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, the mice were euthanized and the hearts, livers, kidneys, and serum were harvested. Gene expression and serum concentration of inflammatory markers were quantified using real-time PCR and ELISA, respectively. DOX treatment significantly suppressed tumor growth in tumor-bearing mice and caused significant cardiac atrophy in tumor-free and tumor-bearing mice. EL4 tumors elicited a strong inflammatory response in the heart, liver, and kidney. Strikingly, DOX treatment ameliorated tumor-induced inflammation paradoxical to the effect of DOX in tumor-free mice, demonstrating a widely divergent effect of DOX treatment in tumor-free versus tumor-bearing mice.
Highlights
Doxorubicin (DOX), known as Adriamycin, is one of the most widely used chemotherapeutic agents in pediatric clinical oncology
We found that the presence of EL4 tumor elicited a strong inflammatory response in multiple organs
No significant morbidity or mortality was observed in either tumor-free or tumor-bearing mice following exposure to DOX (4 mg/kg/week for 3 weeks), which is in agreement with our previous study using the same dose [25]
Summary
Doxorubicin (DOX), known as Adriamycin, is one of the most widely used chemotherapeutic agents in pediatric clinical oncology. Despite its effectiveness in a wide range of cancers including lymphoma, leukemia, and other pediatric cancers, DOX clinical utility is limited due to its multiple organ toxicities. Due to effective cancer treatments, including DOX, the 5 year survival rate of children diagnosed with cancer has increased from less than 60% in the 1970s to more than 80% [8,9]. This leads to a large population of childhood cancer survivors (CCSs), estimated to be around 400,000. CCSs are at high risk of developing long-term adverse effects due to cancer treatment and/or cancer itself
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