Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1992 Nov;98:53–59. doi: 10.1289/ehp.929853

Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.

M Dabholkar 1, L Bradshaw 1, R J Parker 1, I Gill 1, F Bostick-Bruton 1, F M Muggia 1, E Reed 1
PMCID: PMC1519597  PMID: 1486863

Abstract

We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy. Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment. Platinum-DNA adduct levels were measured by atomic absorbance spectrometry. DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA. In a "blinded" study of 21 patients receiving combination cisplatin/carboplatin drug therapy, there was a direct relationship between DNA damage in leukocytes and disease response (summary two-sided p = 0.00011). The cohort of patients had 15 different tumor types, suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor. In leukocytes in vivo, persistence and accumulation were prominent features of the cisplatin-DNA adduct profile. Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro (three, T-cells; three, B-cells; one, monocytic; one, promyelocytic), using a host cell reactivation assay with cisplatin-damaged pRSVcat. In the three T cell lines studied, host cell reactivation efficiency was directly related to the cells' abilities to repair cisplatin-damaged cellular DNA (correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
56

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Dabholkar M., Eastman A., Reed E. Host-cell reactivation of cisplatin-damaged pRSVcat in a human lymphoid cell line. Carcinogenesis. 1990 Oct;11(10):1761–1764. doi: 10.1093/carcin/11.10.1761. [DOI] [PubMed] [Google Scholar]
  2. Fichtinger-Schepman A. M., van Oosterom A. T., Lohman P. H., Berends F. 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 of cis-diamminedichloroplatinum(II). Cancer Res. 1987 Jun 1;47(11):3000–3004. [PubMed] [Google Scholar]
  3. Gill I., Muggia F. M., Terheggen P. M., Michael C., Parker R. J., Kortes V., Grunberg S., Christian M. C., Reed E., den Engelse L. Dose-escalation study of carboplatin (day 1) and cisplatin (day 3): tolerance and relation to leukocyte and buccal cell platinum--DNA adducts. Ann Oncol. 1991 Feb;2(2):115–121. doi: 10.1093/oxfordjournals.annonc.a057872. [DOI] [PubMed] [Google Scholar]
  4. Parker R. J., Eastman A., Bostick-Bruton F., Reed E. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest. 1991 Mar;87(3):772–777. doi: 10.1172/JCI115080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Parker R. J., Poirier M. C., Bostick-Bruton F., Vionnet J., Bohr V. A., Reed E. Peripheral blood leukocytes as a surrogate marker for cisplatin drug resistance: studies of adduct levels and the repair gene ERCC1. Basic Life Sci. 1990;53:251–261. doi: 10.1007/978-1-4613-0637-5_20. [DOI] [PubMed] [Google Scholar]
  6. Reed E. Cisplatin. Cancer Chemother Biol Response Modif. 1991;12:83–90. [PubMed] [Google Scholar]
  7. Reed E., Gupta-Burt S., Litterst C. L., Poirier M. C. Characterization of the DNA damage recognized by an antiserum elicited against cis-diamminedichloroplatinum (II)-modified DNA. Carcinogenesis. 1990 Dec;11(12):2117–2121. doi: 10.1093/carcin/11.12.2117. [DOI] [PubMed] [Google Scholar]
  8. Reed E., Ostchega Y., Steinberg S. M., Yuspa S. H., Young R. C., Ozols R. F., Poirier M. C. Evaluation of platinum-DNA adduct levels relative to known prognostic variables in a cohort of ovarian cancer patients. Cancer Res. 1990 Apr 15;50(8):2256–2260. [PubMed] [Google Scholar]
  9. Reed E., Ozols R. F., Tarone R., Yuspa S. H., Poirier M. C. Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5024–5028. doi: 10.1073/pnas.84.14.5024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Reed E., Ozols R. F., Tarone R., Yuspa S. H., Poirier M. C. The measurement of cisplatin-DNA adduct levels in testicular cancer patients. Carcinogenesis. 1988 Oct;9(10):1909–1911. doi: 10.1093/carcin/9.10.1909. [DOI] [PubMed] [Google Scholar]
  11. Reed E., Yuspa S. H., Zwelling L. A., Ozols R. F., Poirier M. C. Quantitation of cis-diamminedichloroplatinum II (cisplatin)-DNA-intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy. J Clin Invest. 1986 Feb;77(2):545–550. doi: 10.1172/JCI112335. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES