Pediatric blood & cancer · 2018
Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhang Qing-Shuo, Deater Matthew, Phan Ngoc, Marcogliese Andrea, Major Angela, Guinan Eva C, Grompe Markus
Аннотация
BACKGROUND: Fanconi anemia is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Currently, no interventions to prevent or delay the formation of solid tumors are available.
PROCEDURE: Two of the most important hallmarks of Fanconi anemia are inflammation and oxidative stress. In this study, we administrated the antioxidant atorvastatin and the anti-inflammatory drug celecoxib to cohorts of Fancd2-/- /Trp53+/- mice, a model of Fanconi anemia. Treatment started at weaning and continued until the mice developed a palpable mass or suffered from >20% weight loss. Tumor samples and selected tissues were subjected to histopathological examination. χ2 test was performed to analyze tumor incidence, and Kaplan-Meier survival curves were evaluated with log-rank test. In addition, a small cohort of mice was monitored for the safety of the drugs.
RESULTS: The combined oral administration of both drugs significantly delayed tumor onset in Fancd2-/- /Trp53+/- mice. Specifically, the treatment delayed the onset of ovarian tumors in Fancd2-/- /Trp53+/- mice and increased the mean ovarian tumor-free survival time by 17%, whereas this combinatorial drug regimen did not have a significant effect on other tumor types. In addition, no detrimental effects on hematopoiesis from the drug treatment were observed during a 12-month safety monitoring.
CONCLUSIONS: The data presented here suggest that a combination of atorvastatin and celecoxib may be a good candidate for chemoprevention in Fanconi anemia.
PROCEDURE: Two of the most important hallmarks of Fanconi anemia are inflammation and oxidative stress. In this study, we administrated the antioxidant atorvastatin and the anti-inflammatory drug celecoxib to cohorts of Fancd2-/- /Trp53+/- mice, a model of Fanconi anemia. Treatment started at weaning and continued until the mice developed a palpable mass or suffered from >20% weight loss. Tumor samples and selected tissues were subjected to histopathological examination. χ2 test was performed to analyze tumor incidence, and Kaplan-Meier survival curves were evaluated with log-rank test. In addition, a small cohort of mice was monitored for the safety of the drugs.
RESULTS: The combined oral administration of both drugs significantly delayed tumor onset in Fancd2-/- /Trp53+/- mice. Specifically, the treatment delayed the onset of ovarian tumors in Fancd2-/- /Trp53+/- mice and increased the mean ovarian tumor-free survival time by 17%, whereas this combinatorial drug regimen did not have a significant effect on other tumor types. In addition, no detrimental effects on hematopoiesis from the drug treatment were observed during a 12-month safety monitoring.
CONCLUSIONS: The data presented here suggest that a combination of atorvastatin and celecoxib may be a good candidate for chemoprevention in Fanconi anemia.