Sensitization of Resistant Human Tumor Cells to Cisplatin or Carboplatin by Inhibitors of DNA Excision Repair

  • Lode J. Swinnen
  • Nancy Ellis
  • Leonard C. Erickson


Cis-diamminedichloroplatinum(II) (cis-DDP) is one of the most effective drugs currently available for the treatment of human neoplasms. There is compelling evidence that DNA is the drug’s principal biological target.1,2 While the nature and relative frequency of cis-DDP induced DNA adducts have been elucidated3,4 the relative contribution to cytotoxicity and the mechanisms responsible for the repair of each of these lesions remain poorly defined. Understanding the repair systems involved in the removal of cis-DDP induced DNA adducts may well be of fundamental importance in developing strategies for modulating tumor resistance to this drug.


Xeroderma Pigmentosum Interstrand Crosslinking Alkaline Elution Intrastrand Crosslinks Xeroderma Pigmentosum Cell 
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.
    Roberts, J.J., Pera, M.P.: In Neidle, S., and Waring, M.J., (eds.) Molecular Aspects of Anticancer Drug Action, pp 183–231. MacMillan, London, 1983.Google Scholar
  2. 2.
    Sorenson, C.M., Eastman, A., Mechanism of cis-diamminedichloroplatinum(II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks, Cancer Res. 48:4484 (1988).PubMedGoogle Scholar
  3. 3.
    Eastman, A., Reevaluation of interaction of cis-dichloro(ethylenediamine) platinum (II) with DNA, Biochemistry 25:3912 (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    Fichtinger-Schepman, A.M.J., Lohman, P.H.M., Berends, F., Reedijk, J., Van Oosterom, A.T., Interactions of the anti-tumor drug cisplatin with DNA in vitro and in vivo, IARC Scientific Pub. 78:83 (1988).Google Scholar
  5. 5.
    Plooy, A.C., van Dijk, M., Berends, F., Lohman, P.H.M., Formation and repair of DNA interstrand crosslinks in relation to cytotoxicity and unscheduled DNA synthesis induced in control and mutant human cells treated with cis-diamminedichloroplatinum(II), Cancer Res, 45:4178 (1985).PubMedGoogle Scholar
  6. 6.
    Fraval, H.N.A., Rawlings, C.J., Roberts, J. J., Increased sensitivity of UV-repair deficient human cells to DNA bound platinum products which unlike thymine dimers are not recognized by an endonuclease extracted from Micrococcus luteus, Mutation Res. 51:121 (1978).PubMedCrossRefGoogle Scholar
  7. 7.
    Poll, E.H.A., Abrahams, P.J., Arwert, F., Eriksson, A.W., Host-cell reactivation of cis-diamminedichloroplatinum(II)-treated SV40 DNA in normal human, Fanconi anaemia, and Xeroderma pigmentosum fibroblasts, Mutation Res. 132:181 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    Dijt, F.J., Fichtinger-Schepman, A.M.H., Berends, F., Reedijk, J., Formation and repair of cisplatin induced adducts to DNA in cultured normal and repair-deficient human fibroblasts, Cancer Res. 48:6058 (1988).PubMedGoogle Scholar
  9. 9.
    Meyn, R.E., Jenkins, S.F., Thompson, L.H., Defective removal of DNA crosslinks in a repair-deficient mutant of Chinese hamster cells, Cancer Res. 42:3106 (1982).PubMedGoogle Scholar
  10. 10.
    Royer-Pokora B., Gordon, L.K., Haseltine, W.A., Use of exonuclease III to determine the site of stable lesions in defined sequences of DNA: the cyclobutane pyrimidine dimer and cis- and trans-dichlorodiammine platinum(II) examples, Nucleic Acids Res. 9:4595 (1981).PubMedCrossRefGoogle Scholar
  11. 11.
    Beck, D.J., Popoff, S., Sancar, A., Rupp, W.D., Reactions of the UVRABC excision nuclease with DNA damaged by diamminedichloroplatinum(II), Nucleic Acids Res. 13:7395 (1985).PubMedCrossRefGoogle Scholar
  12. 12.
    Husain, I., Chaney, S.G., Sancar, A., Repair of cis-platinum-DNA adducts by ABC excinuclease in vivo and in vitro, J. Bacteriol. 163:817 (1985).PubMedGoogle Scholar
  13. 13.
    Fram, R.J., Cusick, P.S., Marinus, M.G., Studies on mutagenesis and repair induced by platinum analogs, Mutation Res. 173:13 (1986).PubMedCrossRefGoogle Scholar
  14. 14.
    Beck, D.J., Brubaker, R.R.: Effects of cis-platinum(II)diamminedichloride on wild type and deoxyribonucleic acid repair-deficient mutants of Escherichia coli, J. Bacteriol. 116:1247 (1973).PubMedGoogle Scholar
  15. 15.
    Chu, G., Berg, P., DNA crosslinked by cisplatin: a new probe for the repair defect in Xeroderma pigmentosum, Mol. Biol. Med. 4:227 (1987).Google Scholar
  16. 16.
    Chu, G., Chang, E. Xeroderma pigmentosum group E cells lack a nuclear factor that binds to damaged DNA, Science 242:564 (1988).PubMedCrossRefGoogle Scholar
  17. 17.
    Stone, P.J. Kelman, A.D., Sinex, F.M., Specific binding of antitumor drug cis-Pt(NH3)2Cl2 to DNA rich in guanine and cytosine, Nature 251:736 (1974).PubMedCrossRefGoogle Scholar
  18. 18.
    Roberts, J.J., Friedlos, F., Quantitative aspects of the formation and loss of DNA interstrand crosslinks in Chinese hamster cells following treatment with cis-diamminedichloroplatinum(II) (cisplatin) 1. Proportion of DNA-platinum reactions involved in DNA crosslinking, Biochim. Biophys. Acta. 655:146 (1981).PubMedCrossRefGoogle Scholar
  19. 19.
    Zwelling, L.A., Michaels, S., Schwartz, H., Dobson, P.O., Kohn, K.W., DNA crosslinking as an indicator of sensitivity and resistance of mouse L1210 leukemia to cis-diamminedichloroplatinum(II) and L-phenylalanine mustard, Cancer Res. 41:640 (1981).PubMedGoogle Scholar
  20. 20.
    Roberts, J. J., Friedlos, F., Quantitative estimation of cisplatin-induced DNA interstrand crosslinks and their repair in mammalian cells: relationship to toxicity, Pharmac. Ther. 34:215 (1987).CrossRefGoogle Scholar
  21. 21.
    Pinto, A.L. Lippard, S.J., Sequence-dependent termination of in vitro DNA synthesis by cis- and trans-diamminedichloroplatinum(II), Proc. Natl. Acad. Sci. USA 82:4616 (1985).PubMedCrossRefGoogle Scholar
  22. 22.
    Cohen, G.L., Ledner, J.A., Bauer, W.R., Ushay, H.M., Caravana, C., Lippard, S.J., Sequence dependent binding of cis-dichlorodiammineplatinum(II) to DNA, J. Am. Chem. Soc. 102:2487 (1980).CrossRefGoogle Scholar
  23. 23.
    Stone, P.J., Kelman, A.D., Sinex, F.M., Bhargava, M.M., Halvorson, H.O., Resolution of α, β, and DNA of Saccharomyces cerevisiae with the antitumor drug cis-Pt(NH3)2 Cl2. Evidence for preferential drug binding by GpG sequences of DNA, J. Mol. Biol. 104:793 (1976).PubMedCrossRefGoogle Scholar
  24. 24.
    Swinnen, L.J., Barnes, D.M., Fisher, S.G., Albain, K.S., Fisher, R.I., Erickson, L.C., 1-β-D-Arabinofuranosylcytosine and hydroxyurea produce cytotoxic synergy with cis-diamminedichloroplatinum(II) and modifications in platinum-induced DNA interstrand crosslinking, Cancer Res. 49:1383 (1989).PubMedGoogle Scholar
  25. 25.
    Snyder, R.D., Carrier, W.L., Regan, J.D., Application of Arabinofuranosylcytosine in the kinetic analysis and quantitation of DNA repair in human cells after ultraviolet irradiation, Biophys. J. 35:339 (1981).PubMedCrossRefGoogle Scholar
  26. 26.
    Fogh, J., Trempe, G.: In Fogh, J. (ed.) Human Tumor Cells in vitro, pp 115–159. Plenum Press, New York, 1975.CrossRefGoogle Scholar
  27. 27.
    Kohn, K.W., Ewig, R., Erickson, L.C., Zwelling, L.A., Measurement of strand breaks and crosslinks in DNA by alkaline elution, in: “DNA Repair: A Laboratory Manual of Research Techniques,” Friedberg, E.C. and Hanawalt, P.C., eds. Dekker, New York (1981).Google Scholar
  28. 28.
    Regan, J.D. Setlow, R.B., Ley, R.D., Normal and defective repair of damaged DNA in human cells: a sensitive assay utilizing the photolysis of bromodeoxyuridine, Proc. Nat. Acad. Sci. USA 68:708 (1971).PubMedCrossRefGoogle Scholar
  29. 29.
    Regan, J.D. Setlow, R.B., Kaback, M.M., Howell, R.R., Klein, E., Burgess, G., Xeroderma pigmentosum: a rapid sensitive method for prenatal diagnosis, Science 174:147 (1971).PubMedCrossRefGoogle Scholar
  30. 30.
    Cleaver, J.E., Repair processes for photochemical damage in mammalian cells, in: “Advances in Radiation Biology,” Lett, J.T., Adler, H., and Zelle, M., eds. Academic Press, New York (1974).Google Scholar
  31. 31.
    Fornace Jr., A., Kohn, K.W., Kann, H.E., DNA single-strand breaks during repair of UV damage in human fibroblasts and abnormalities of repair in Xeroderma pigmentosum, Proc. Nat. Acad. Sci. USA 73:39 (1976).PubMedCrossRefGoogle Scholar
  32. 32.
    Regan, J.D. Trosko, J.E., Carrier, W.L., Evidence for excision of ultraviolet-induced pyrimidine dimers from the DNA of human cells in vitro, Biophys. J. 8:319 (1968).PubMedCrossRefGoogle Scholar
  33. 33.
    Zwelling, L.A. Anderson, T., Kohn, K.W., DNA-protein and DNA interstrand crosslinking by cis- and trans-platinum(II)diamminedichloride in L1210 mouse leukemia cells and relation to cytotoxicity, Cancer Res. 39:365 (1979).PubMedGoogle Scholar
  34. 34.
    Yoshida, S., Yamada, M. and Masaki, S., Inhibition of DNA polymerase α-and β-of calf thymus by 1-β-D-Arabinofuranosylcytosine-5′-triphosphate, Biochim. et Biophys. Acta, 477:144 (1977).CrossRefGoogle Scholar
  35. 35.
    Dunn, W.C., and Regan, J.D., Inhibition of DNA excision repair in human cells by Arabinofuranosylcytosine: effect on normal and Xeroderma pigmentosum cells, Mol. Pharmacol. 15:367 (1979).PubMedGoogle Scholar
  36. 36.
    Hiss, E.A. and Preston, R.J., The effect of cytosine arabinoside on the frequency of single-strand breaks in DNA of mammalian cells following irradiation or chemical treatment, Biochim. et Biophys. Acta, 478:1 (1977).CrossRefGoogle Scholar
  37. 37.
    Major, P.P., Egan, E.M., Herrick, D.J., Kufe, D.W., The effect of Ara-C incorporation on DNA synthesis, Biochem. Pharmacol. 31:2937 (1982).PubMedCrossRefGoogle Scholar
  38. 38.
    Kufe, D.W., Weishselbaum, R., Egan, E.M., Dahlberg, W., and Fram, R.J., Lethal Effects of 1-β-D-Arabinofuranosylcytosine incorporation into DNA during UV repair, Mol. Pharmacol. 25:322 (1984).PubMedGoogle Scholar
  39. 39.
    Kufe, D.W., Munroe, D., Herrick, D., Egan, E., Spriggs, D., Effects of 1-β-D-Arabinofuranosylcytosine incorporation on eukaryotic DNA template function, Molecular Pharm. 26:128 (1984).Google Scholar
  40. 40.
    Erixon, K., and Ahnstrom, G., Single strand breaks in DNA during repair of UV-induced damage in normal human and Xeroderma pigmentosum cells as determined by alkaline DNA unwinding and hydroxylapatite chromatography, Muta. Res. 59:257 (1979).CrossRefGoogle Scholar
  41. 41.
    Fram, R.J. and Kufe, D.W., DNA strand breaks caused by inhibitors of DNA synthesis: 1-β-D-Arabinofuranosylcytosine and aphidicolin, Cancer Res. 42:4050 (1982).PubMedGoogle Scholar
  42. 42.
    Fram, R.J., and Kufe, D.W., Effect of Ara-C and hydroxyurea on the repair of X-ray-induced DNA single-strand breaks in human leukemic blasts, Biochem. Pharmacol. 34:2557 (1985).PubMedCrossRefGoogle Scholar
  43. 43.
    Snyder, R.D., Carrier, W.L., Regan, J.D., Application of Arabinofuranosylcytosine in the kinetic analysis and quantitation of DNA repair in human cells after ultraviolet irradiation, Biophys. J. 35:339 (1981).PubMedCrossRefGoogle Scholar
  44. 44.
    Collins, A.R.S., Schor, S.L., and Johnson, R.T., The inhibition of repair in UV irradiated human cells, Muta. Res. 42:413 (1977).CrossRefGoogle Scholar
  45. 45.
    Robichaud, N.J., Fram, R.J., Potentiation of Ara-C induced cytotoxicity by hydroxyurea in LoVo colon carcinoma cells, Biochem. Pharmacol. 36:1673 (1987).PubMedCrossRefGoogle Scholar
  46. 46.
    Bergerat, J.P., Drewinko, B., Corry, P., Barlogie, B., and Ho, D.H., Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-β-D-Arabinofuranosylcytosine, Cancer Res. 41:25 (1981).PubMedGoogle Scholar
  47. 47.
    Schabel, F.M., “Annual Progress Report of the Southern Research Institute”, Section II, p 9, Birmingham, AL (1979).Google Scholar
  48. 48.
    Burchenal, J.H., O’Toole, T., Kalaher, K., and Chisholm, J., Synergistic effects of the combination of cis-platinum diamminedichloride and 2,2′-anhydro-1-β-D-arabinofuranosyl-5-fluorocytosine in transplanted mouse leukemias, Cancer Res. 37:4098 (1977).PubMedGoogle Scholar
  49. 49.
    Vadi, H., and Drewinko, B., Kinetics and mechanism of the 1-β-D-Arabinofuranosylcytosine-induced potentiation of cis-diamminedichloroplatinum(II) cytotoxicity, Cancer Res. 46:1105 (1986).PubMedGoogle Scholar
  50. 50.
    Fram, R.J., Robichaud, N., Bishov, S.D., Wilson, J.M., Interactions of cis-diamminedichloroplatinum(II) with 1-β-D Arabinofuranosylcytosine in LoVo colon carcinoma cells, Cancer Res. 47:3360 (1987).PubMedGoogle Scholar
  51. 51.
    Swinnen, L.J. Fisher, S.G., Erickson, L.C., Ultraviolet irradiation produces cytotoxic synergy and increased DNA interstrand crosslinking with cis- and trans-diamminedichloroplatinum(II), Carcinogenesis 10:1465 (1989).PubMedCrossRefGoogle Scholar
  52. 52.
    Micetich, K.C., Barnes, D.M., Erickson, L.C., A comparative study of the cytotoxicity and DNA damaging effects of cis-(diammino) (1,1 cyclobutane-dicarboxylato)-platinum(II) and cis-diamminedichloroplatinum(II) on L1210 cells, Cancer Res. 45:4043 (1985).PubMedGoogle Scholar
  53. 53.
    Swinnen, L.J., Ellis, N., Erickson, L.C., Inhibition of cis-diammine 1,1-cyclobutane dicarboxylato platinum(II) (CBDCA)-induced DNA interstrand crosslink removal and potentiation of CBDCA cytotoxicity by hydroxyurea and 1-β-D-arabinofuranosylcytosine (Ara-C), Cancer Res. in press (1991).Google Scholar
  54. 54.
    Albain, K.S. Swinnen, L. J., Erickson, L.C, Stiff, P.J., Fisher, R.I., Cisplatin preceded by concurrent cytarabine and hydroxyurea: A pilot based upon an in vitro model, Cancer Chemo. Pharm. 27:33 (1990).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Lode J. Swinnen
    • 1
  • Nancy Ellis
    • 1
  • Leonard C. Erickson
    • 1
  1. 1.Section of Hematology/Oncology, Department of Medicine, Stritch School of MedicineLoyola University ChicagoMaywoodUSA

Personalised recommendations