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.
Numazawa
Satoshi
S
Department of Biochemical Toxicology, Showa University School of Pharmacy, Shinagawa, Tokyo, Japan. numazawa@pharm.showa-u.ac.jp
Sugihara
Kazuko
K
Miyake
Shota
S
Tomiyama
Hirono
H
Hida
Ayako
A
Hatsuno
Misato
M
Yamamoto
Masayuki
M
Yoshida
Takemi
T
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005472:Fluorouracil / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress
D007166:Immunosuppressive Agents; D051547:Heme Oxygenase-1; D005978:Glutathione; D005472:Fluorouracil; D000111:Acetylcysteine