RESUMO
BACKGROUND AND AIM: 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 of 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-2mg /kg and CPS-50mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed. RESULTS: Co-treatment of 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. CONCLUSION: 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.
RESUMO
Dexamethasone-induced Ras-related protein 1 (Rasd1) is a member of the Ras superfamily of monomeric G proteins that have a regulatory function in signal transduction. Rasd1, also known as Dexras1 or AGS1, is rapidly induced by dexamethasone (Dex). While prior data indicates that Rasd1 is highly expressed in the pituitary and that the gene may function in regulation of corticotroph activity, its exact cellular localization in this tissue has not been delineated. Nor has it been determined which endocrine pituitary cell type(s) are responsive to Dex-induced expression of Rasd1. We hypothesized that Rasd1 is primarily localized in corticotrophs and furthermore, that its expression in these cells would be upregulated in response to exogenous Dex administration. Rasd1 expression in each pituitary cell type both under basal conditions and 1-hour post Dex treatment were examined in adult male mice. While a proportion of all endocrine pituitary cell types expressed Rasd1, a majority of corticotrophs and thyrotrophs expressed Rasd1 under basal condition. In vehicle treated animals, approximately 50-60% of corticotrophs and thyrotrophs cells expressed Rasd1 while the gene was detected in only 15-30% of lactotrophs, somatotrophs, and gonadotrophs. In Dex treated animals, Rasd1 expression was significantly increased in corticotrophs, somatotrophs, lactotrophs, and gonadotrophs but not thyrotrophs. In Dex treated animals, Rasd1 was detected in 80-95% of gonadotrophs and corticotrophs. In contrast, Dex treatment increased Rasd1 expression to a lesser extent (55-60%) in somatotrophs and lactotrophs. Corticotrophs of the pars intermedia, which lack glucocorticoid receptors, failed to display increased Rasd1 expression in Dex treated animals. Rasd1 is highly expressed in corticotrophs under basal conditions and is further increased after Dex treatment, further supporting its role in glucocorticoid negative feedback. In addition, the presence and Dex-induced expression of Rasd1 in endocrine pituitary cell types, other than corticotrophs, may implicate Rasd1 in novel pituitary functions.