Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1993 Mar;99:149–154. doi: 10.1289/ehp.9399149

Platinum drug-DNA interactions in human tissues measured by cisplatin-DNA enzyme-linked immunosorbent assay and atomic absorbance spectroscopy.

M C Poirier 1, E Reed 1, H Shamkhani 1, R E Tarone 1, S Gupta-Burt 1
PMCID: PMC1567012  PMID: 8319613

Abstract

Studies of platinum drug-DNA adduct formation in tissues of cancer patients have involved both atomic absorbance spectroscopy (AAS), which measures total DNA-bound platinum, and anti-cisplatin-DNA enzyme-linked immunosorbent assay (ELISA), which detects a fraction of the AAS-measurable adduct. These studies were designed to explore mechanisms of drug-DNA interactions, to make correlations with clinical outcome, and possibly to validate DNA adduct measurements for use in occupational and environmental biomonitoring. The results, determined by both ELISA and AAS, demonstrate that cisplatin and its analog carboplatin bind to DNA in many human organs, including kidney, brain, peripheral nerve, and bone marrow, which are sites for drug toxicity. Platinum was also observed bound to ovarian tumor DNA. The adducts were highly persistent, being measurable in tissues obtained at autopsy up to 15 months after the last administration of platinum chemotherapy. A comparison of blood cell DNA adduct levels, determined by ELISA, and the clinical response of 139 patients with ovarian, testicular, colon, or breast cancer demonstrated a strong correlation between failure to form DNA adducts and failure of therapy. Conversely, patients who formed high levels of DNA adduct were most likely to respond favorably. A similar correlation was not observed for adducts determined by AAS; that is, the average total DNA-bound platinum levels were the same for patients who did not respond to therapy and for patients who had any kind of response. Thus, in this study, human blood cell DNA adducts measured by ELISA correlate with tumor remission, while those measured by AAS do not.

Full text

PDF
149

Selected References

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

  1. Calvert A. H., Horwich A., Newlands E. S., Begent R., Rustin G. J., Kaye S. B., Harris A. L., Williams C. J., Slevin M. L. Carboplatin or cisplatin? Lancet. 1988 Sep 3;2(8610):577–578. doi: 10.1016/s0140-6736(88)92709-2. [DOI] [PubMed] [Google Scholar]
  2. Dijt F. J., Fichtinger-Schepman A. M., Berends F., Reedijk J. Formation and repair of cisplatin-induced adducts to DNA in cultured normal and repair-deficient human fibroblasts. Cancer Res. 1988 Nov 1;48(21):6058–6062. [PubMed] [Google Scholar]
  3. Fichtinger-Schepman A. M., Baan R. A., Berends F. Influence of the degree of DNA modification on the immunochemical determination of cisplatin-DNA adduct levels. Carcinogenesis. 1989 Dec;10(12):2367–2369. doi: 10.1093/carcin/10.12.2367. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Fichtinger-Schepman A. M., van der Velde-Visser S. D., van Dijk-Knijnenburg H. C., van Oosterom A. T., Baan R. A., Berends F. Kinetics of the formation and removal of cisplatin-DNA adducts in blood cells and tumor tissue of cancer patients receiving chemotherapy: comparison with in vitro adduct formation. Cancer Res. 1990 Dec 15;50(24):7887–7894. [PubMed] [Google Scholar]
  6. Kato S., Yamashita K., Kim T., Tajiri T., Onda M., Sato S. Modification of DNA by mitomycin C in cancer patients detected by 32P-postlabeling analysis. Mutat Res. 1988 Nov;202(1):85–91. doi: 10.1016/0027-5107(88)90167-4. [DOI] [PubMed] [Google Scholar]
  7. Poirier M. C., Lippard S. J., Zwelling L. A., Ushay H. M., Kerrigan D., Thill C. C., Santella R. M., Grunberger D., Yuspa S. H. Antibodies elicited against cis-diamminedichloroplatinum(II)-modified DNA are specific for cis-diamminedichloroplatinum(II)-DNA adducts formed in vivo and in vitro. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6443–6447. doi: 10.1073/pnas.79.21.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Poirier M. C., Reed E., Litterst C. L., Katz D., Gupta-Burt S. Persistence of platinum-ammine-DNA adducts in gonads and kidneys of rats and multiple tissues from cancer patients. Cancer Res. 1992 Jan 1;52(1):149–153. [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. Reedijk J., Lohman P. H. Cisplatin: synthesis, antitumour activity and mechanism of action. Pharm Weekbl Sci. 1985 Oct 25;7(5):173–180. doi: 10.1007/BF02307573. [DOI] [PubMed] [Google Scholar]
  15. Souliotis V. L., Kaila S., Boussiotis V. A., Pangalis G. A., Kyrtopoulos S. A. Accumulation of O6-methylguanine in human blood leukocyte DNA during exposure to procarbazine and its relationships with dose and repair. Cancer Res. 1990 May 1;50(9):2759–2764. [PubMed] [Google Scholar]
  16. Yang X. Y., Gasparro F. P., DeLeo V. A., Santella R. M. 8-Methoxypsoralen-DNA adducts in patients treated with 8-methoxypsoralen and ultraviolet A light. J Invest Dermatol. 1989 Jan;92(1):59–63. doi: 10.1111/1523-1747.ep13071224. [DOI] [PubMed] [Google Scholar]

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

RESOURCES