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Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals

  • Original Article
  • Cisplatin, DNA Crosslinking, DNA Repair, Ageing
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Abstract

DNA interstrand crosslinks (ISCL) produced by the incubation of human peripheral blood mononuclear cells (PBMs) with cisplatin (CDDP) were measured in two populations of volunteers, one aged less than 25 years and the other, greater than 72 years. The technique of fluorometric alkaline elution was used to measure DNA interstrand crosslinking with time after a 1-h exposure to drug. The samples from the young group showed a more consistent pattern of crosslink formation and removal, with extensive, or in some cases complete, repair at 48 h. Those from the elderly group showed considerable inter-individual variation and significantly higher mean levels of crosslinking at 24 and 48 h. No samples showed complete repair at 48 h in this population. These results indicate an impaired DNA repair capacity in the cells from the elderly group. This may be a factor in the poor tolerance of chemotherapy in the ageing population

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References

  1. Newell G, Spitz M, Sider J (1989) Cancer and age. Semin Oncol 16:3–9

    CAS  PubMed  Google Scholar 

  2. Ozols RF, Young RC (1985) High dose cisplatin therapy in ovarian cancer. Semin Oncol 12:21–30

    CAS  PubMed  Google Scholar 

  3. Fox EP, Loehrer (1991) Chemotherapy for advanced testicular cancer. Hematol Oncol Clin North Am 5:1173–1187

    CAS  PubMed  Google Scholar 

  4. Medias NE, Harrington JT (1978) Platinum nephrotoxicity. Am J Med 65:307–314

    Article  Google Scholar 

  5. Roelofs RI, Hrushersky W, Rogin J, et al (1984) Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology 34: 934–938

    Article  CAS  PubMed  Google Scholar 

  6. Roberts JJ, Pera MF (1983) DNA as a target for anticancer compounds. In: Lippard SJ (ed) Platinum, gold, and other metal chemotherapeutic agents. American Chemical Society, Washington, DC, pp 3–25

    Chapter  Google Scholar 

  7. Roberts JJ, Knox RJ, Pera MF, et al (1988) The role of platinum-DNA interactions in the cellular toxicity and anti-tumor effects of platinum corrdination compounds. In: Nicolini M (ed) Platinum and other metal coordination compounds in cancer chemotherapy. Nijhoff, Boston, pp 16–31

    Chapter  Google Scholar 

  8. Zwelling LA, Anderson T, Kohn KW (1979) DNA-protein and DNA interstrand cross-linking bycis andtrans platinum (II) diamminedichloride in L1210 mouse leukemia cells and relationship to cytotoxicity. Cancer Res 39:365–369

    CAS  PubMed  Google Scholar 

  9. Zwelling LA, Michaels S, Schwartz H, Dobson PP, Kohn KW (1981) DNA crosslinking as an indicator of sensitivity and resistance of mouse L1210 leukemia tocis-diamminedichloroplatinum(II) andl-phenyalanine mustard. Cancer Res 41:640–649

    CAS  PubMed  Google Scholar 

  10. Reed E, Behrens BC, Yuspa SH, et al (1986) Differences in cisplatin-DNA adduct formation in sensitive and resistant sublines of human ovarian cancer cells (abstract 1132). Proc AACR 27:285

    Google Scholar 

  11. Eastman A (1986) Re-evaluation of interaction ofcis-dichlo(ethylenediamine)platinum(II) with DNA. Biochemistry 25:3912–3915

    Article  CAS  PubMed  Google Scholar 

  12. Plooy ACM, Fichtinger-Schlepman AMJ, Schutte HH, et al (1985) The quantitative detection of various Pt-DNA adducts in Chinese hamster ovary cells treated with cisplatin: application of immunochemical techniques. Carcinogenesis 6:561–566

    Article  CAS  PubMed  Google Scholar 

  13. Fichtinger-Schepman AMJ AT Oosterom van, Lohman PHM, Berends F (1987)cis-Diamminedichloroplatinum (II)-induced DNA adducts in peripheral leukocytes from seven cancer patients: quantitative immunochemical detection of the adduct induction and removal after a single dose ofcis-diamminedichloroplatinum. Cancer Res 47:3000–3004

    CAS  PubMed  Google Scholar 

  14. Fichtinger-Schlepman AMJ, Dijt FJ, De Jong WH, et al (1988) In vivo as diamminedichloroplatinum (II)-DNA adduct formation and removal as measured with immunochemical techniques. In: Nicolini M (ed) Platinum and other metal coordination compounds in cancer chemotherapy. Nijhoff, Boston, pp 32–46

    Chapter  Google Scholar 

  15. Pera MF, Rawlings CJ, Roberts JJ (1981) The role of DNA repair in the recovery of human cells from cisplatin toxicity. Chem Biol Interact 37:245–261

    Article  CAS  PubMed  Google Scholar 

  16. Bedford P, Fitchtinger-Schlepman AMJ, Shellard SA, et al (1988) Differential repair of platinum-DNA adducts in human bladder and testicular tumour continuous cell lines. Cancer Res 48:3019–3024

    CAS  PubMed  Google Scholar 

  17. Kohn KW, Ewig RAG, Erickson LC, Zwelling LA (1981) Measurement of strand breaks and cross-links by alkaline elution. In: Friedberg EC, Hanawalt PC (eds) DNA repair, vol 1B. Dekker, New York, pp 379–403

    Google Scholar 

  18. Stout DL, Becker FF (1982) Fluorometric quantitation of single stranded DNA: a method applicable to the technique of alkaline elution. Anal Biochem 127:302–307

    Article  CAS  PubMed  Google Scholar 

  19. Tice R, Setlow R (1985) DNA repair and replication in aging organisms and cells. In: Finch CE, Schneides EL (eds) Handbook of biology of aging, 2nd edn. van Nostrand Reinhold, New York

    Google Scholar 

  20. Mullaart E, Boerrigter ME, Lohman PH, Vijg J (1989) Age-related induction and disappearance of carcinogen-DNA-adducts in livers of rats exposed to low levels of 2-acetylaminofluorene. Chem Biol Interact 69:373–384

    Article  CAS  PubMed  Google Scholar 

  21. Fort F, Cerutti P (1981) Altered DNA repair in fibroblasts from aged rats. Gerontology 27:306–313

    Article  CAS  PubMed  Google Scholar 

  22. Kutlaca R, Seshadri R, Morley A (1982) Effect of age on sensitivity of human lymphocytes to radiation. A brief note. Mech Age Dev 19:97–101

    Article  CAS  Google Scholar 

  23. Prieur M, et al (1988) Acquired chromosome rearrangements in human lymphocytes: effect of aging. Hum Genet 79:147–150

    Article  CAS  PubMed  Google Scholar 

  24. Knox RJ, Friedlos F, Lydall DJ, Roberts JJ (1986) Mechanisms of cytotoxicity of anticancer platinum drugs: evidence thatcis-diamminedichloroplatinum andcis-diammine-(1,1-cyclobutanedicarboxyplato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res 46 1972–1979

    CAS  PubMed  Google Scholar 

  25. Reed E, Yuspa SH, Zwelling L, Ozols RF, Poirier MC (1986) Quantitation ofcis-diamminedichloroplatinum 11 (cisplatin)-DNA interstrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy. J Clin Invest 77: 545–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Reed E, Ozols RF, Tatone R, Yuspa SH, Poirier MC (1987) Platinum-DNA adducts in leucocyte DNA correlate with disease response in ovarian cancer patients receiving platinum based chemotherapy. Proc Natl Acad Sci USA 84 5024–5028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhen W, Link C, O'Connor P, et al. (1992) Increased genespecific repair of cisplatin interstrand cross-links in cisplatinresistant human ovarian cancer cell lines. Mol Biol 12: 3689–3698

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, University College London Medical School, 91 Riding House Street, W1P8BT, London, UK

    G. N. Rudd, J. A. Hartley & R. L. Souhami

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  1. G. N. Rudd
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  2. J. A. Hartley
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  3. R. L. Souhami
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Rudd, G.N., Hartley, J.A. & Souhami, R.L. Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals. Cancer Chemother. Pharmacol. 35, 323–326 (1995). https://doi.org/10.1007/BF00689452

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  • DOI: https://doi.org/10.1007/BF00689452

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