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Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent Cu-diacetyl-bis(N 4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells

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Abstract

The retention mechanism of the novel imaging/radiotherapeutic agent, Cu-diacetyl-bis(N 4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells was clarified in comparison with that in normal tissuein vitro. With Cu-ATSM and reversed phase HPLC analysis, the reductive metabolism of Cu-ATSM in subcellular fractions obtained from Ehrlich ascites tumor cells was examined. As a reference, mouse brain was used. To determine the contribution of enzymes in the retention mechanisms, and specific inhibitor studies were performed. In subcellular fractions of tumor cells, Cu-ATSM was reduced mainly in the microsome/cytosol fraction rather than in the mitochondria. This finding was completely different from that found in normal brain cells. The reduction process in the microsome/cytosol was heat-sensitive and enhanced by adding exogenous NAD(P)H, an indication of enzymatic reduction of Cu-ATSM in tumor cells. Among the known bioreductive enzymes. NADH-cytochrome b5 reductase and NADPH-cytochrome P450 reductase in microsome played a major role in the reductive retention of Cu-ATSM in tumors. This enzymatic reduction was enhanced by the induction of hypoxia. Radiocopper labeled Cu-ATSM provides useful information for the detection of hypoxia as well as the microsomal bioreductive enzyme expression in tumor.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Atsushi Obata, Eiji Yoshimi & Hideo Saji

  2. Mallinckrodt Institute of Radiology, Washington University Medical Center, St. Louis, U.S.A.

    Jason S. Lewis, Nobuyuki Oyama & Michael J. Welch

  3. Biomedical Imaging Research Center, Fukui Medical University, Matsuoka, 910-1193, Fukui, Japan

    Atsushi Obata, Atsuo Waki, Yoshiharu Yonekura & Yasuhisa Fujibayashi

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  1. Atsushi Obata
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  2. Eiji Yoshimi
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  3. Atsuo Waki
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  4. Jason S. Lewis
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  5. Nobuyuki Oyama
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  6. Michael J. Welch
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  7. Hideo Saji
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  8. Yoshiharu Yonekura
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  9. Yasuhisa Fujibayashi
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Correspondence to Yasuhisa Fujibayashi.

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Obata, A., Yoshimi, E., Waki, A. et al. Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent Cu-diacetyl-bis(N 4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells. Ann Nucl Med 15, 499–504 (2001). https://doi.org/10.1007/BF02988502

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  • DOI: https://doi.org/10.1007/BF02988502

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