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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)

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.

Keywords

Nucleoside Analog Phosphoramide Mustard Rapid Repair Ethidium Bromide Fluorescence Dose Reduction Index 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Chen TL, Passos-Coetho JL, Noe DA, Kennedy MJ, Black KC, Colvin M, Grochow BL (1995) Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous marrow transplantation. Cancer Res., 18: 810–816Google Scholar
  2. 2.
    Schuler U, Ehninger G, Wagner T (1987) Repeated high-dose cyclophosphamide administration in bone marrow transplantation: exposure to activated metabolites. Cancer Chemother Pharmacol., 20: 248–252PubMedCrossRefGoogle Scholar
  3. 3.
    Yule SM, Boddy AV, Cole M, Price L, Wyllie R, Tasso MJ, Pearson ADJ, Idle JR (1995) Cyclophosphamide metabolism in children. Cancer Res., 55: 803–809PubMedGoogle Scholar
  4. 4.
    Rowley SD, Jones RJ, Piantadosi S, Braine HG, Colvin OM, Davis J, Saral R, Sharkis S, Ingard J, Yeager AM, Santos GW (1989) Efficacy of ex vivo purging for autologous bone marrow transplantation in the treatment of acute nonlymphoblastic leukemia. Blood 74: 501–506PubMedGoogle Scholar
  5. 5.
    DeNeve W, Valeriote F, Edelstein M, Everett C, Bischoff M (1989) In Vivo DNA Cross-Linking by cyclophosphamide: Comparison of human chronic lymphatic leukemia cells with mouse L1210 leukemia and normal bone marrow cells. Cancer Res., 49: 3452–3456PubMedGoogle Scholar
  6. 6.
    Wang JY, Porok G, Vaughan WP (1993) Cytotoxicity, DNA cross-linking, and DNA single-strand breaks induced by cyclophosphamide in rat leukemia in vivo. Cancer Chemother Pharmacol., 31: 381–386PubMedCrossRefGoogle Scholar
  7. 7.
    Dong Q, Borsky D, Colvin ME, Melius C, Ludemann S, Moravek JF, Colvin OM, Bigner DD, Modrich P, Friedman HS (1995) A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5’-d(GAC). Biochemistry., 92: 12170–12174Google Scholar
  8. 8.
    Povirk LF, Shuker DE (1994) DNA damage and mutagenesis induced by nitrogen mustards. Mutation Res., 318: 205–226PubMedGoogle Scholar
  9. 9.
    Andersson BS, Mroue M, Britten RA, Murray D (1994) The role of DNA damage in the resistance of human chronic myeloid leukemia cells to cyclophosphamide analogues. Cancer Res., 54: 5394–5400PubMedGoogle Scholar
  10. 10.
    Garcia ST, McQuillan A, Panasci L (1988) Correlation between the cytotoxicity of Melphalan and DNA crosslinks as detected by the ethidium bromide fluorescence assay in the F1 variant of B16 melanoma cells. Biochem Pharmacol., 37: 3189–3192PubMedCrossRefGoogle Scholar
  11. 11.
    Kastan MB, Schlaffer E, Russo JE, Colvin OM, Civin CI, Hilton J (1990) Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood 10: 1947–1950Google Scholar
  12. 12.
    McGrown AT, Fox BW (1986) A proposed mechanism of resistance to cyclophosphamide and phosphoramide mustard in aYoshida cell line in vitro. Cancer Chemother Pharmacol., 17: 223–226Google Scholar
  13. 13.
    Calsou P, Salles B (1993) Role of DNA repair in the mechanisms of cell resistance to alkylating agents and cisplatin. Cancer Chemother Pharmacol., 32: 85–89PubMedCrossRefGoogle Scholar
  14. 14.
    Larminat F, Zhen W, Bohr AV (1993) Gene-specific DNA repair of interstrand cross-links induced by chemotherapeutic agents can be preferential. Biol Chemistry., 208: 2649–2654Google Scholar
  15. 15.
    Hemminski K, Ludlum DB (1984) Covalent modification of DNA by antineoplastic agents. J Natl Cancer Inst., 73: 1021–1028Google Scholar
  16. 16.
    Dong Q, Bullock N, Ali-Osman F, Colvin M, Signer DD, Friedman HS (1996) Repair analysis of 4-hydroperoxycyclophosphamide-induced interstrand crosslinking in the c-myc gene in 4hydroperoxycyclophosphamide-sensitive and -resistant medulloblastoma cell lines. Cancer Chemother Pharmacol., 37: 242–246PubMedCrossRefGoogle Scholar
  17. 17.
    Keating M, O’Brien S, Plunkett W, Robertson LE, Gandhi V, Estey E, Dimopoulos M, Cabanillas F, Kemena A, Kantarjian H (1994) Fludarabine posphate: A new active agent in hematologic malignancies. Sem Hematol., 31: 28–39Google Scholar
  18. 18.
    Keating M, McLaughlin P, Plunkett W, Robertson LE, O’Brien S, Gandhi V, Gregoire V, Yang L, Cabanillas F (1994) Fludarabine–present status and future developments in chronic lymphocytic leukemia and lymphoma. Annals Oncol., 5: 79–83Google Scholar
  19. 19.
    Plunkett W, Gandhi V, Huang P, Robertson LE, Yang LY, Gregoire V, Estey E, Keating M (1993) Fludarabine: pharmacokinetics, mechanisms of action and rationales for combination therapies. Sem Oncology., 10: 2–12Google Scholar
  20. 20.
    Huang P, Plunkett W (1995) Fludarabine-and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol., 36: 181–188PubMedCrossRefGoogle Scholar
  21. 21.
    Tseng WC, Derse D, Cheng YC, Brockman RW, Bennett LL (1982) In vitro activity of 9- ß-Darabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol., 21: 474–477PubMedGoogle Scholar
  22. 22.
    Catapano C, Perrino FW, Fernandes DJ (1993) Primer RNA chain termination induced by 9ß-D-arabinofuranosyl-2-fluoro adenine 5-triphosphate: a mechanism of DNA synthesis inhibition. J Biol Chem., 268: 7179–7185PubMedGoogle Scholar
  23. 23.
    Kamiya K, Huang P, Plunkett W (1996) Inhibition of the 3–5 exonuclease of human DNA polymerase £ by fludarabine-terminated DNA. Biolog Chemistry., 271: 19428–19435CrossRefGoogle Scholar
  24. 24.
    Lozzio GB, Lozzio BB (1975) Human chronic myelogenious leukemia cell line with positive Philadelphia chromosome. Blood., 45: 321–326PubMedGoogle Scholar
  25. 25.
    Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationship: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul., 22: 27–55PubMedCrossRefGoogle Scholar
  26. 26.
    Chou TC, Talalay P (1988) Computerized simulation of dose reduction index (DRI) in synergistic drug combinations. Pharmacologist., 30: A231Google Scholar
  27. 27.
    Brent TP (1984) Supression of cross-link foramation in chloroethylnitrosourea-treated DNA by an activity in extracts of human leukemic lymphoblasts. Cancer Res., 44: 1887–1892PubMedGoogle Scholar
  28. 28.
    Yang LY, Li L, Keating MJ, Plunkett W (1995) Arabinofuranosyl-2-fluoroadenine augments cisplatin cytotoxicity and inhibits cisplatinDNA cross-link repair. Molecular Pharmacol., 47: 1072–1079Google Scholar
  29. 29.
    Chresta CM, Crook TR, Souhami RL (1990) Depletion of cellular glutathione by N,N’-bis (trans-4-hydroxycyclohexyl)-N’-nitrosourea as a determinant of sensitivity of K562 human leukemia cells to 4-Hydroperoxycyclophosphamide. Cancer Res., 50: 4067–4071PubMedGoogle Scholar
  30. 30.
    Crook TR, Souhami RL, McLean AEM (1986) Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells. Cancer Res., 46: 5029–5034PubMedGoogle Scholar
  31. 31.
    Little SA, Mirkes PE (1987) DNA cross-linking and single-strand breaks induced by teratogenic concentrations of 4-hydroperoxycyclophosphamide and phosphoramide mustard in post-implantation rat embryos. Cancer Res., 47: 5421–5426PubMedGoogle Scholar
  32. 32.
    Hengstler JH, Fuchs J, Oesch F (1992) DNA strand breaks and DNA cross-links in peripherial mononuclear blood cells of ovarian cancer patients during chemotherapy with cyclophosphamide/carboplatin. Cancer Res., 52: 5622–5626PubMedGoogle Scholar
  33. 33.
    Hilton J (1984) Deoxyribonucleic acid cross-linking by 4-hydroperoxycyclophosphamide in cyclophosphamide-sensitive and resistant L1210 Cells. Biochem Pharmacol., 12: 1867–1872CrossRefGoogle Scholar
  34. 34.
    Keating M, O’Brien S, McLaughlin P, Kantarjian H, Cabanillas F (1996) Fludarabine combinations in the management of chronic lymphocytic leukemia and low grade lymphoma. Annals of Oncology., 34, 110Google Scholar
  35. 35.
    Reed E, Kohn EC, Sarosy G, Dabholkar M, Davis P, Jacob J, Martha M (1995) Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer: Molecular rationale and early clinical results. Seminars in Oncology., 3: 90–96Google Scholar
  36. 36.
    Cleaver JE (1994) It was a very good year for DNA repair. Cell., 76: 1–4PubMedCrossRefGoogle Scholar

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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