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Possible Involvement of Oxidative Stress in 5‐Fluorouracil‐Mediated Myelosuppression in Mice
Author(s) -
Numazawa Satoshi,
Sugihara Kazuko,
Miyake Shota,
Tomiyama Hirono,
Hida Ayako,
Hatsuno Misato,
Yamamoto Masayuki,
Yoshida Takemi
Publication year - 2011
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2010.00621.x
Subject(s) - oxidative stress , bone marrow , glutathione , pharmacology , antioxidant , chemotherapy , oxidative phosphorylation , acetylcysteine , myeloid , medicine , cancer research , chemistry , biochemistry , enzyme
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.