Hypersensitivity to Cisplatin in Mouse Leukemia L1210/0 Cells: An XPG DNA Repair Defect

  • Richard D. Wood
  • Juhani A. Vilpo
  • Leena M. Vilpo
  • David E. Szymkowski
  • Anne O’Donovan
  • Jonathan G. Moggs


A major limitation to the clinical efficacy of cisplatin is the intrinsic or acquired resistance of many neoplasms to the drug. As a result, many studies to investigate the mechanisms of cisplatin resistance have been carried out with human and rodent cells in culture. Acquired resistance has been ascribed in different cases to changes in drug accumulation, intracellular drug inactivation by enhanced levels of glutathione or metallothionein, and enhanced DNA repair.


L1210 Cell Xeroderma Pigmentosum L1210 Cell Line Repair Synthesis Imperial Cancer Research Fund 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A. Aboussekhra and R.D. Wood, Repair of ultraviolet light-damaged DNA by mammalian cells and Saccharomyces cerevisiae. Curr. Opin. Genet. Devel., 4:212 (1994).CrossRefGoogle Scholar
  2. 2.
    J. Hansson, S.M. Keyse, T. Lindahl and R.D. Wood, DNA excision repair in cell extracts from human cell lines exhibiting hypersensitivity to DNA damaging agents. Cancer Res., 51:3384 (1991).PubMedGoogle Scholar
  3. 3.
    D.E. Szymkowski, K. Yarema, J.E. Essigmann, S.J. Lippard and R.D. Wood, An intrastrand d(GpG) platinum crosslink in duplex M13 DNA is refractory to repair by human cell extracts. Proc. Natl. Acad. Sci. USA, 89:10772 (1992).CrossRefPubMedGoogle Scholar
  4. 4.
    L. Law, T. Dunn, P. Boyle and J. Miller, Observation on the effect of a folic-acid antagonist on transplantable lymphoid leukemias in mice. J. Natl. Cancer Inst., 10:179 (1949).PubMedGoogle Scholar
  5. 5.
    G. Moore, A. Sandberg and K. Ulrich, Suspension cell culture and in vivo and in vitro chromosome constitution of mouse leukemia L1210. J. Natl. Cancer. Inst., 36:405 (1966).PubMedGoogle Scholar
  6. 6.
    J.H. Burchenal, K. Kalaher, T. O’Toole and J. Chisholm, Lack of cross-resistance between certain platinum coordination compounds in mouse leukemia. Cancer Res., 37:3455 (1977).PubMedGoogle Scholar
  7. 7.
    J. Burchenal, K. Kalaher, L. Lokys and G. Gale, Studies of cross-resistance, synergistic combinations and blocking of activity of platinum derivatives. Biochimie, 60:961 (1978).CrossRefGoogle Scholar
  8. 8.
    V. Richon, N. Schulte and A. Eastman, Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells. Cancer Res., 47:2056 (1987).PubMedGoogle Scholar
  9. 9.
    N. Sheibani, M.M. Jennerwein and A. Eastman, DNA repair in cells sensitive and resistant to cis-diamminedichloroplatinum(II): host cell reactivation of damaged plasmid DNA. Biochemistry, 28:3120 (1989).CrossRefPubMedGoogle Scholar
  10. 10.
    A. Eastman and N. Schulte, Enhanced DNA repair as a mechanism of resistance to cis-diamminedichloroplatinum(II). Biochemistry, 27:4730 (1988).CrossRefPubMedGoogle Scholar
  11. 11.
    J.A. Vilpo, L.M. Vilpo, D.E. Szymkowski, A. O’Donovan and R.D. Wood, An XPG DNA repair defect causing mutagen hypersensitivity in mouse leukemia L1210 cells. Mol. Cell Biol., 15:290 (1995).PubMedGoogle Scholar
  12. 12.
    G. Weeda and J.H.J. Hoeijmakers, Genetic analysis of nucleotide excision repair in mammalian cells. Semin. Cancer Biol., 4:105 (1993).PubMedGoogle Scholar
  13. 13.
    J. Hansson, M. Munn, W.D. Rupp, R. Kahn and R.D. Wood, Localization of DNA repair synthesis by human cell extracts to a short region at the site of a lesion. J. BioL Chem., 264:21788 (1989).PubMedGoogle Scholar
  14. 14.
    A. O’ Donovan and R.D. Wood, Identical defects in DNA repair in xeroderma pigmentosum group G and rodent ERCC group 5. Nature, 363:185 (1993).CrossRefGoogle Scholar
  15. 15.
    R.D. Wood, P. Robins and T. Lindahl, Complementation of the xeroderma pigmentosum DNA repair defect in cell-free extracts. Cell, 53:97 (1988).CrossRefPubMedGoogle Scholar
  16. 16.
    M. Biggerstaff, D.E. Szymkowski and R.D. Wood, Co-correction of the ERCC1, ERCC4 and xeroderma pigmentosum group F DNA repair defects in vitro. EMBO J, 12:3685 (1993).PubMedGoogle Scholar
  17. 17.
    D. Scherly, T. Nouspikel, J. Corlet, C. Ucla, A. Bairoch and S.G. Clarkson, Complementation of the DNA repair defect in xeroderma pigmentosum group G cells by a human cDNA related to yeast RAD2. Nature, 363:182 (1993).CrossRefPubMedGoogle Scholar
  18. 18.
    T. Shiomi, Y.-n. Harada, T. Saito, N. Shiomi, Y. Okuno and M. Yamaizumi, An ERCC5 gene with homology to yeast RAD2 is involved in group G xeroderma pigmentosum. Mutat. Res., 314:167 (1994).CrossRefPubMedGoogle Scholar
  19. 19.
    M.A. MacInnes, J.A. Dickson, R.R. Hernandez, D. Learmonth, G.Y. Lin, J.S. Mudgett, M.S. Park, S. Schauer, R.J. Reynolds, G.F. Strniste and J.Y. Yu, Human ERCC5 cDNA-cosmid complementation for excision repair and bipartite amino acid domains conserved with RAD proteins of Saccharomyces cerevisiae and Schizosaccharomyces pombe. Mol. Cell BioL, 13:6393 (1993).PubMedGoogle Scholar
  20. 20.
    A. O’ Donovan, D. Scherly, S.G. Clarkson and R.D. Wood, Isolation of active recombinant XPG protein, a human DNA repair endonuclease. J. Biol. Chem., 269:15965 (1994).Google Scholar
  21. 21.
    T. Nouspikel and S.G. Clarkson, Mutations that disable the DNA repair gene XPG in a xeroderma pigmentosum group G patient. Hum. Molec. Genet., 3:963 (1994).CrossRefPubMedGoogle Scholar
  22. 22.
    J.E. Cleaver, F. Cortes, L.H. Lutze, W.F. Morgan, A.N. Player and D.L. Mitchell, Unique DNA repair properties of a xeroderma pigmentosum revertant. Mol. Cell. BioL, 7:3353 (1987).PubMedGoogle Scholar
  23. 23.
    A. O’ Donovan, A.A. Davies, J.G. Moggs, S.C. West and R.D. Wood, XPG endonuclease makes the 3’ incision in human DNA nucleotide excision repair. Nature, 371:432 (1994).CrossRefGoogle Scholar
  24. 24.
    Y. Habraken, P. Sung, L. Prakash and S. Prakash, Human xeroderma-pigmentosum group-G gene encodes a DNA endonuclease. Nucleic Acids Res, 22:3312 (1994).CrossRefPubMedGoogle Scholar
  25. 25.
    J.J. Harrington and M.R. Lieber, Functional domains within FEN-1 and Rad2 define a family of structure-specific endonucleases — implications for nucleotide excision-repair. Genes Dev, 8:1344 (1994).CrossRefPubMedGoogle Scholar
  26. 26.
    P. Robins, D.J.C. Pappin, R.D. Wood and T. Lindahl, Structural and functional homology between mammalian DNase IV and the 5′ nuclease domain of Escherichia coli DNA polymerase I. J. Biol. Chem., 269:28535 (1994).PubMedGoogle Scholar
  27. 27.
    M.M. Jennerwein, A. Eastman and A.R. Khokhar, The role of DNA-repair in resistance of L1210 cells to isomeric 1,2-diaminocyclohexaneplatinum complexes and ultraviolet-irradiation. Mutat. Res., 254:89 (1991).CrossRefPubMedGoogle Scholar
  28. 28.
    A.F. Nichols, W.J. Schmidt, S.G. Chaney and A. Sancar, Limitations of the in vitro repair synthesis assay for probing the role of DNA repair in platinum resistance. Chem. Biol. Interact., 81:223 (1992).CrossRefPubMedGoogle Scholar
  29. 29.
    P. Calsou, J.-M. Barret, S. Cros and B. Salles, DNA excision-repair synthesis is enhanced in a murine leukemia L1210 cell line resistant to cisplatin. Eur. J. Biochem., 211:403 (1993).CrossRefPubMedGoogle Scholar
  30. 30.
    G.R. Gibbons, J.D. Page, S.K. Mauldin, I. Husain and S.G. Chaney, Role of carrier ligand in platinum resistance in L1210 cells. Cancer Research, 50:6497 (1990).PubMedGoogle Scholar
  31. 31.
    G. Gibbons, W. Kaufman and S. Chaney, Role of DNA replication in carrier-ligand-speciflc resistance to platinum compounds in L1210 cells. Carcinogenesis, 12:2253 (1991).CrossRefPubMedGoogle Scholar
  32. 32.
    N. Farrell, Y. Qu, L. Feng and B. Van Houten, Comparison of chemical reactivity, cytotoxicity, interstrand cross-linking and DNA sequence specificity of bis(platinum) complexes containing monodentate or bidentate coordination spheres with their monomeric analogues. Biochemistry, 29:9522 (1990).CrossRefPubMedGoogle Scholar
  33. 33.
    N. Farrell, Y. Qu and M.P. Hacker, Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes. J Med Chem, 33:2179 (1990).CrossRefPubMedGoogle Scholar
  34. 34.
    N. Farrell, L.R. Kelland, J.D. Roberts and M.V. Beusichem, Activation of the trans geometry in platinum antitumor complexes: a survey of the cytotoxicity of trans complexes containing planar ligands in murine L1210 and human tumor panels and studies on their mechanism of action. Cancer Res., 52:5065 (1992).PubMedGoogle Scholar
  35. 35.
    L.R. Kelland, P. Mistry, G. Abel, S.Y. Loh, CF. O’ Neill, B.A. Murrer and K.R. Harrap, Mechanism-related circumvention of acquired cis-diarnminedichloroplatinum(II) resistance using 2 pairs of human ovarian-carcinoma cell-lines by ammine amine platinum(IV) dicarboxylates. Cancer. Res., 52:3857 (1992).PubMedGoogle Scholar
  36. 36.
    P.A. Andrews and S.B. Howell, Cellular pharmacology of cisplatin — perspectives on mechanisms of acquired-resistance. Canc. Cells, 2:35 (1990).Google Scholar
  37. 37.
    H. Timmer-Bosscha, N. Mulder and E. de Vries, Modulation of cis-diamminedichloroplatinum(II) resistance: a review. Brit J Cancer, 66:227 (1992).CrossRefPubMedGoogle Scholar
  38. 38.
    G. Chu, Cellular-responses to cisplatin — the roles of DNA-binding proteins and DNA-repair. J Biol Chem, 269:787 (1994).PubMedGoogle Scholar
  39. 39.
    D. Coverley, M.K. Kenny, D.P. Lane and R.D. Wood, A role for the human single-stranded DNA binding protein HSSB/RPA in an early stage of nucleotide excision repair. Nucleic Acids Res., 20:3873 (1992).CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Richard D. Wood
    • 1
  • Juhani A. Vilpo
    • 1
  • Leena M. Vilpo
    • 1
  • David E. Szymkowski
    • 1
  • Anne O’Donovan
    • 1
  • Jonathan G. Moggs
    • 1
  1. 1.Clare Hall LaboratoriesImperial Cancer Research FundSouth Mimms, HertsUK

Personalised recommendations