Fludarabine-Mediated Circumvention of Cytarabine Resistance Is Associated with Fludarabine Triphosphate Accumulation in Cytarabine-Resistant Leukemic Cells
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概要
- 論文の詳細を見る
The combination of cytarabine (ara-C) with fludarabine is a common approach to treating resistant acute myeloid leukemia. Success depends on a fludarabine triphosphate (F-ara-ATP)-mediated increase in the active intracellular metabolite of ara-C, ara-C 5'-triphosphate (ara-CTP). Therapy-resistant leukemia may exhibit ara-C resistance, the mechanisms of which might induce cross-resistance to fludarabine with reduced F-ara-ATP formation. The present study evaluated the effect of combining ara-C and fludarabine on ara-C-resistant leukemic cells in vitro. Two variant cell lines (R1 and R2) were 8-fold and 10-fold more ara-C resistant, respectively, than the parental HL-60 cells. Reduced deoxycytidine kinase activity was demonstrated in R1 and R2 cells, and R2 cells also showed an increase in cytosolic 5'-nucleotidase II activity. Compared with HL-60 cells, R1 and R2 cells produced smaller amounts of ara-CTP. Both variants accumulated less F-ara-ATP than HL-60 cells and showed cross-resistance to fludarabine nucleoside (F-ara-A). R2 cells, however, accumulated much smaller amounts of F-ara-ATP and were more F-ara-A resistant than R1 cells. In HL-60 and R1 cells, F-ara-A pretreatment followed by ara-C incubation produced F-ara-ATP concentrations sufficient for augmenting ara-CTP production, thereby enhancing ara-C cytotoxicity. No potentiation was observed in R2 cells. Nucleotidase might preferentially degrade F-ara-A monophosphate over ara-C monophosphate, leading to reduced F-ara-ATP production and thereby compromising the F-ara-A-mediated potentiation of ara-C cytotoxicity in R2 cells. Thus, F-ara-A-mediated enhancement of ara-C cytotoxicity depended on F-ara-ATP accumulation in ara-C-resistant leukemic cells but ultimately was associated with the mechanism of ara-C resistance.
- 日本血液学会の論文
- 2007-02-15
著者
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Ueda Takanori
福井大学 血液腫瘍内科学
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Ueda T
Department Of Hematology And Oncology University Of Fukui
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YAMAMOTO Shuji
Department of Radiology, Osaka University Hospital
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Yabe Aya
Department Of Molecular Biology Institute Of Gerontology Nippon Medical School
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KISHI Shinji
Department of Pediatrics, Nagoya City University Medical School
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YOSHIDA AKIRA
Department of Radiological Sciences, Hiroshima Prefectural College of Health Science
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Ueda T
Department Of Urology Chiba Cancer Center
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Kishi Shinji
福井大学 医学部第一内科
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Kishi S
First Department Of Internal Medicine Fukui Medical University
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Ueda T
First Department Of Internal Medicine University Of Fukui
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Kuraishi Yasunobu
国立金沢病院
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Kuraishi Yasunobu
Idarubicin Study Group Internal Medicine Iii Jikei University School Of Medicine
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Yamauchi T
Department Of Hematology And Oncology University Of Fukui
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Ueda Takanori
Department of Cardiology, University of Fukui Hospital
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Yamauchi Takahiro
福井大学 血液腫瘍内科学
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YAMAUCHI Takahiro
Department of Hematology and Oncology, University of Fukui
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KAWAI Yasukazu
Department of Hematology and Oncology, University of Fukui
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TAKEMURA Haruyuki
Department of Hematology and Oncology, University of Fukui
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URASAKI Yoshimasa
Department of Hematology and Oncology, University of Fukui
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IWASAKI Hiromichi
Department of Hematology and Oncology, University of Fukui
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Yamauchi Takahiro
Department Of Hematology And Oncology University Of Fukui
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Yoshida Akira
First Department Of Internal Medicine University Of Fukui
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Yoshida A
Department Of Applied Biological Sciences School Of Agricultural Sciences Nagoya University
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Ueda Takahiro
First Department Of Internal Medicine Fukui Medical University Idarubicin Study Group
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Kishi Shinji
First Department Of Internal Medicine University Of Fukui
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Kishi Shinji
Department Of Pediatrics Nagoya City University Medical School
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Urasaki Yoshimasa
First Department Of Internal Medicine University Of Fukui
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Kawai Yasukazu
Department Of Hematology And Oncology University Of Fukui
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Yoshida A
First Department Of Internal Medicine University Of Fukui
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Iwasaki Hiromichi
Department Of Hematology And Oncology University Of Fukui
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Takemura Haruyuki
Department Of Hematology And Oncology University Of Fukui
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Ueda Takeshi
Department Of Urology Chiba University Graduate School Of Medicine
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Yoshida Akira
Department Of Cardiology Mitsubishi Kyoto Hospital
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Kawai Yasukazu
Department Of Cell Pathology Graduate School Of Medical Sciences Kumamoto University
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Yamamoto Shuji
Department Of Hematology And Oncology University Of Fukui
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Yoshida Akira
Department Of Cardiology Kyoto National Hospital
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Yoshida Akira
Department Of Agricultural Chemistry Nagoya University
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Yamamoto Shuji
Department of Applied Chemistry, Yamanashi University
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