Possible involvement of oxidative stress in 5-fluorouracil-mediated myelosuppression in mice

Certain chemotherapeutic agents subject cells to oxidative stress, thereby promoting adverse effects. However, the molecular machinery governing 5-fluorouracil (5-FU)-mediated myelotoxicity is obscure. The purpose of this study was to clarify whether 5-FU-induced myelotoxicity is a cause of oxidative stress. Treatment of mice with 5-FU (75 mg/kg, i.p.) caused a significant induction of haem oxygenase-1 and a decrease in glutathione contents in bone marrow cells, both of which are the indicators of oxidative stress. The 5-FU-mediated decrease in the myeloid colony formation was intensified in Nrf2^-/- mice, in which antioxidant proteins were down-regulated. N-Acetylcysteine reversed the 5-FU-induced decreases in the glutathione content, number of bone marrow cells per femur and myeloid colony formation. Results from the present study reveal that 5-FU induces oxidative stress in bone marrow, which is involved, at least in part, in myelotoxicity in mice. Therefore, Nrf2-dependent genes as well as glutathione levels in bone marrow could be therapeutic targets for decreasing such side-effects in 5-FU-based chemotherapy.