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Effect of Combined Treatment with 4-Hydroperoxycyclophosphamide and Fludarabine on Cytotoxicity and Repair of Damaged DNA

  • Conference paper
Acute Leukemias VII

Part of the book series: Haematology and Blood Transfusion / Hämatologie und Bluttransfusion ((HAEMATOLOGY,volume 39))

Abstract

For treatment with cyclophosphamide (CP) rapid repair of CP-induced DNA interstrand cross-links (ICLs) seems to be an important problem in the lack of activity. This implies the idea of combined treatment of CP with nucleoside analogs such as fludarabine or gemcitabine,which should be able to inhibit repair of damaged DNA. Using multiple drug effect analysis we investigated the interaction between the cyclophosphamide prodrug 4-HC and the nucleoside of fludarabine, F-ara-A. Simultaneous exposure to the drug combination 4-HC/F-ara-A for 4 h resulted in synergistic reduction of clonogenicity in the lymphoblastic cell line CCRF-CEM. This finding was in agreement with repair experiments of 4-HC induced ICLs.After 4 h exposure to 10 µM 4-HC alone and washing into drug-free media, more than 80% of the ICLs were repaired after 6 h. In contrast, the retention of ICLs was increased in cells incubated with 4-HC in combination with F-ara-A, such that most of ICLs remained after 6 h. These results suggest a possible role of nucleoside analogs to suppress the repair of damaged DNA. This maybe a mechanistic basis for the synergistic cytotoxicity of combined treatment with alkylating agents and nucleoside analogs.

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Author information

Authors and Affiliations

  1. Department of Clinical Investigation, UTMD Anderson Cancer Center, Houston, Texas, USA

    U. Koehl, B. Nowak, V. Ruiz Van Haperen, M. Keating & W. Plunkett

  2. Department of Laboratory Medicine, Houston, Texas, USA

    L. Ying Yang & L. Li

  3. Department of Pediatric Oncology, University Hospital, Frankfurt, Germany

    U. Koehl

Authors
  1. U. Koehl
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  2. L. Ying Yang
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  3. L. Li
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  4. B. Nowak
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  5. V. Ruiz Van Haperen
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  6. M. Keating
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  7. W. Plunkett
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Editor information

Editors and Affiliations

  1. Department of Internal Medicine, University of Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany

    W. Hiddemann  & B. Wörmann  & 

  2. Department of Internal Medicine, USA

    T. Büchner

  3. Department of Pediatrics, University of Münster, Albert-Schweitzer-Straße 33, 48149, Münster, Germany

    J. Ritter  & U. Creutzig  & 

  4. Dept. of Hematology, University of Texas, Anderson Cancer Center, 1515 Holcombe Boulevard, 77030, Houston, Tx., USA

    M. Keating MD PhD  & W. Plunkett MD PhD  & 

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© 1998 Springer-Verlag Berlin Heidelberg

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Koehl, U. et al. (1998). Effect of Combined Treatment with 4-Hydroperoxycyclophosphamide and Fludarabine on Cytotoxicity and Repair of Damaged DNA. In: Hiddemann, W., et al. Acute Leukemias VII. Haematology and Blood Transfusion / Hämatologie und Bluttransfusion, vol 39. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71960-8_73

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  • DOI: https://doi.org/10.1007/978-3-642-71960-8_73

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-71962-2

  • Online ISBN: 978-3-642-71960-8

  • eBook Packages: Springer Book Archive

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