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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4300-4307.
Prepublished online as a Blood First Edition Paper on August 24, 2004; DOI 10.1182/blood-2004-04-1631.
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Submitted April 29, 2004
Accepted August 9, 2004
Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity and restores indicators in an in vivo mouse model of anemia of chronic disease
Yoko Nakano, Shigehiko Imagawa*, Ken Matsumoto, Christian Stockmann, Naoshi Obara, Norio Suzuki, Takeshi Doi, Tatsuhiko Kodama, Satoru Takahashi, Toshiro Nagasawa, and Masayuki Yamamoto
Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan
Institute fur Physiologie, Universitatsklinikum Essen, Essen, Germany
Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan
Tokyo New Drug Research LaboratoriesII, Kowa Co., Ltd., Tokyo, Japan
Laboratory for Systems Biology and Medicine Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan
Division of Anatomy and Embryology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan
* Corresponding author; email: simagawa{at}md.tsukuba.ac.jp.
Erythropoietin (Epo) gene expression is under the control of hypoxia-inducible factor 1 (HIF-1), and is negatively regulated by GATA. Interleukin 1 (IL-1) and tumor necrosis factor  (TNF-), which increase the binding activity of GATA and inhibit Epo promoter activity, are increased in patients with anemia of chronic disease (ACD). We previously demonstrated the ability of K-7174 (a GATA-specific inhibitor), when injected intraperitoneally, to improve Epo production that had been inhibited by IL-1 or TNF- treatment. In the present study, we examined the ability both K-11706, which inhibits GATA and enhances HIF-1 binding activity, and K-13144, which has no effect on GATA or HIF-1 binding activity, to improve Epo production following inhibition by IL-1 or TNF- in Hep3B cells in vitro and in an in vivo mouse assay. Oral administration of K-11706 reversed the decreases in hemoglobin and serum Epo concentrations, reticulocyte counts and numbers of erythroid colony-forming unit (CFU-E) induced by IL-1 or TNF-. These results raise the possibility of using orally administered K-11706 for treating patients with ACD.
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