1.A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice
Satyanarayana R Pondugula ; Julia M Salamat ; Kodye L Abbott ; Patrick C Flannery ; Mohammed Majrashi ; Mohammed Almaghrabi ; Manoj Govindarajulu ; Sindhu Ramesh ; Maninder Sandey ; Suneel K Onteru ; Chen-Che J Huang ; Yoshimi Iwaki ; Kristina Gill ; Natasha Narayanan ; Edwin McElroy ; Darshini Desai ; Rishi Nadar ; Timothy Moore ; Muralikrishnan Dhanasekaran
Liver Research 2021;5(4):239-242
Background and aims
Chronic exposure to chemotherapeutics can lead to severe adverse events including hepatotoxicity. A combination chemotherapy regimen of doxorubicin (DOX) and cyclophosphamide (CPS) is employed in treatment of several cancers such as leukemia, lymphoma, and breast cancer. It is not well understood whether a combination therapy with DOX and CPS can induce hepatotoxicity. We therefore sought to determine whether co-administration of DOX and CPS at their clinically relevant doses and frequency results in hepatotoxicity.
Methods
Male C57BL/6J mice received one intraperitoneal injection of saline or DOX-2 mg/kg and CPS-50 mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed.
Results
Co-treatment with DOX and CPS did not alter the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, globulin, or total protein. Similarly, co-administration of DOX and CPS did not result in a noticeable change in liver histology. However, it was notable that the concomitant treatment with DOX and CPS resulted in a significant increase in serum levels of aspartate aminotransferase (AST). Elevated serum AST levels were also associated with increased serum creatinine kinase (CK) levels, suggesting that the elevated serum AST levels are likely due to muscle injury following the co-administration of DOX and CPS.
Conclusions
Taken together, our results, for the first time, suggest that co-administration of DOX and CPS, at their clinically relevant doses and frequency does not induce a significant hepatotoxicity in the mice.
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