Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model.

Abstract

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. 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. 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. The data presented here suggest that a combination of atorvastatin and celecoxib may be a good candidate for chemoprevention in Fanconi anemia.