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Selective Treatment of Hypoxic Tumor Cells In Vivo: Phosphate Pre-Prodrugs of Nitro Analogues of the Duocarmycins

Authors

  • Dr. Moana Tercel,

    Corresponding author
    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
    • Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Graham J. Atwell,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Dr. Shangjin Yang,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Dr. Amir Ashoorzadeh,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Dr. Ralph J. Stevenson,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • K. Jane Botting,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Dr. Yongchuan Gu,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Sunali Y. Mehta,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Prof. William A. Denny,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Prof. William R. Wilson,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • Dr. Frederik B. Pruijn

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9373-7502
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  • This research was funded by the Foundation for Research, Science and Technology, NZ, and Proacta. We thank Sisira Kumara, Maruta Boyd, Sally Bai, Wouter van Leeuwen, and Caroline McCulloch for technical assistance.

Abstract

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Hitting the hypoxic target: Combining a nitro prodrug with a water-soluble phosphate converts duocarmycin analogues from highly toxic DNA-alkylating agents to highly selective antitumor compounds. These prodrugs (see scheme) have outstanding activity against hypoxic tumor cells in vivo, cells which are usually considered the most resistant to conventional therapy.

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