Examining tissue-level changes in Doxorubicin accumulation and Nitric Oxide formation in skeletal muscle and tumours in a mouse model of breast cancer.

Abstract

Introduction: Doxorubicin is a commonly used chemotherapy that rapidly accumulates in skeletal muscle and disrupts nitric oxide (NO) formation. However, studies investigating these effects have largely been performed in tumour-free models, therefore it remains unknown whether intramuscular accumulation and disruptions to nitric oxide content persist during tumour growth.

Methodology: Female C57bl/6 mice (n = 8/group) were randomly assigned to true control, Doxorubicin control, tumour only, or tumour plus Doxorubicin groups. Tumours were grown for 21, 24, or 28 days using E0771 cells. Doxorubicin was administered as a single 10 mg/kg intraperitoneal dose on day 21.

Results: Doxorubicin accumulation was similar in muscle with and without tumours present. Doxorubicinol, a metabolite of Doxorubicin, was elevated (p<0.05) in 24-day tumour+Doxorubicin compared to Doxorubicin alone. NO was similar across all groups in muscle; however, tumour NO was 15-fold higher at day 21 compared to 24, or 28 days (p<0.05).

Conclusion: The results confirm that Doxorubicin is sequestered in skeletal muscle when a tumour is present, which may impact bioavailability. Tumour growth transiently increased intramuscular Doxorubicinol, potentially exacerbating the toxicity of the drug. Earlier stage tumour growth appeared to profoundly elevate NO, which could suggest temporal angiogenesis and vasodilation to facilitate growth.