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

  • U. Koehl
  • L. Ying Yang
  • L. Li
  • B. Nowak
  • V. Ruiz Van Haperen
  • M. Keating
  • W. Plunkett
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 39)


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.


Nucleoside Analog Phosphoramide Mustard Rapid Repair Ethidium Bromide Fluorescence Dose Reduction Index 
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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • U. Koehl
    • 1
    • 3
  • L. Ying Yang
    • 2
  • L. Li
    • 2
  • B. Nowak
    • 1
  • V. Ruiz Van Haperen
    • 1
  • M. Keating
    • 1
  • W. Plunkett
    • 1
  1. 1.Department of Clinical InvestigationUTMD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Laboratory MedicineHoustonUSA
  3. 3.Department of Pediatric OncologyUniversity HospitalFrankfurtGermany

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