Improvement of iron-mediated oxidative DNA damage in patients with transfusion-dependent myelodysplastic syndrome by treatment with deferasirox.
Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias, and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA damage. However, it is uncertain how iron-mediated oxidative stress affects the pathophysiology of MDS. This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000 ng/mL or they required more than 20 RBC transfusions (or 100 mL/kg of RBC). We prospectively analyzed 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients.
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Shohei
S
Kikuchi
Masayoshi
M
Kobune
Satoshi
S
Iyama
Tsutomu
T
Sato
Kazuyuki
K
Murase
Yutaka
Y
Kawano
Kohichi
K
Takada
Kaoru
K
Ono
Yumiko
Y
Kaneko
Koji
K
Miyanishi
Yasushi
Y
Sato
Tsuyoshi
T
Hayashi
Rishu
R
Takimoto
Junji
J
Kato
D000080242:8-Hydroxy-2'-Deoxyguanosine; D015703:Antigens, CD; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D004249:DNA Damage; D000077588:Deferasirox; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D017707:Erythrocyte Transfusion / Q000009:adverse effects*; D005293:Ferritins / Q000097:blood; D015894:Genome, Human; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019190:Iron Overload / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy*; D011446:Prospective Studies; D017382:Reactive Oxygen Species / Q000097:blood; D018709:Statistics, Nonparametric; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
D015703:Antigens, CD; D001565:Benzoates; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D014230:Triazoles; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005293:Ferritins; D003849:Deoxyguanosine; D000077588:Deferasirox