Skip to main content
SpringerLink
Log in

Mechanisms of Tamoxifen-Induced Genotoxicity and Carcinogenicity

  • Conference paper
Book cover Hormonal Carcinogenesis II

  • 66 Accesses

Abstract

Tamoxifen is an anti-estrogen widely used with proven efficacy in the treatment of breast cancer in women (1). It is well tolerated and has potentially beneficial actions in reducing serum cholesterol (2) and the incidence of fatal heart attacks (3). Preliminary results suggest that tamoxifen will reduce the incidence of breast cancer in such women (2). However, several epidemiological studies in women with breast cancer have shown that tamoxifen can also lead to increased incidence of endometrial tumors (4–6). Although tamoxifen is primarily an antiestrogen, it also has some estrogenic properties. At present, it is not clear whether the effect on the endometrium is due to estrogen-like stimulation by tamoxifen, causing cell proliferation and the promotion of endogenous lesions, or a direct mutagenic effect on the affected cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Cummings FJ, Gray R, Tormey DC, et al. (1993) Adjuvant tamoxifen versus placebo in elderly women with node-positive breast cancer: Long-term follow-up and causes of death. J Clin Oncol 11:29–35.

    PubMed  CAS  Google Scholar 

  2. Powles TJ, Jones AL, Ashley SE, et al. (1994) The Royal Marsden Hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res Treat 31:73–82.

    Article  PubMed  CAS  Google Scholar 

  3. McDonald CC, Stewart HJ (1991) Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. Brit Med J 303:435–437.

    Article  PubMed  CAS  Google Scholar 

  4. Marshall E (1994) Tamoxifen: Hanging in the balance. Science 264:1524–1527.

    Article  PubMed  CAS  Google Scholar 

  5. Jordan VC (1988) Tamoxifen and endometrial cancer. Lancet 2:1019

    PubMed  CAS  Google Scholar 

  6. Fornander T, Rutqvist LE, Wilking N (1991) Effects of tamoxifen on the female genital tract. Ann N Y Acad Sei USA 622:469–473.

    Article  CAS  Google Scholar 

  7. Tucker MJ, Adams HK, Patterson JS (1984) Tamoxifen. In Laurence DR, McLean AEM, Weatherall M (eds): Safety Testing of New Drugs. New York: Academic Press, pp 125–161.

    Google Scholar 

  8. Greaves P, Goonetilleke R, Nunn G, et al. (1993) Two-year carcinogenicity study of tamoxifen in Alderly Park Wistar-derived rats. Cancer Res 53:3919–3924.

    PubMed  CAS  Google Scholar 

  9. Hard GC, Iatropoulos MJ, Jordan K, et al. (1993) Major differences in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. Cancer Res 53:4534–4541.

    PubMed  CAS  Google Scholar 

  10. Hirsimaki P, Hirsimaki Y, Nieminen L, et al. (1993) Tamoxifen induces hepatocellular carcinoma in rat liver-A 1-year study with 2 antiestrogens. Arch Toxicol 67:49–54.

    Article  PubMed  CAS  Google Scholar 

  11. Jordan VC, Robinson SP (1987) Species-specific pharmacology of antiestrogens: Role of metabolism. Fed eration Proc 46:1870–1874.

    CAS  Google Scholar 

  12. White INH, De Matteis F, Davies A, et al. (1992) Genotoxic potential of tamoxifen and analogues in female Fischer F344/N rats, DBA/2 and C57B1/6 mice and in human MCL-5 cells. Carcinogenesis 13:2197–2203.

    Article  PubMed  CAS  Google Scholar 

  13. Dahme E, Rattel B (1994) Unlike tamoxifen, droloxifene produces no hepatic tumors in the rat. Onkologie 17:6–16.

    Article  Google Scholar 

  14. Carthew P, Martin EA, White INH, et al. (1995) Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: Promotion by phenobarbital. Cancer Res 55:544–547.

    PubMed  CAS  Google Scholar 

  15. Carthew P, Rich KJ, Martin EA, et al. (1995) DNA damage as assessed by 32P-postlabelling in three rat stains exposed to dietary tamoxifen: The relationship between cell proliferation and liver tumour formation. Carcinogenesis, in press.

    Google Scholar 

  16. Carthew P, Martin EA, White INH, et al. (1995) Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: Promotion by phenobarbital. Cancer Res 55:544–547.

    PubMed  CAS  Google Scholar 

  17. White INH, Davies A, Smith LL, et al. (1993) Induction of CYP2B1 and 3A1, and associated monooxygenase activities by tamoxifen and certain analogues in the livers of female rats and mice. Biochem Pharmacol 45:21–30.

    Article  PubMed  CAS  Google Scholar 

  18. Lim CK, Yuan Z, Lamb JH, et al. (1994) A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes. Carcinogenesis 15:589–593.

    Article  PubMed  CAS  Google Scholar 

  19. Martin EA, Rich K, White INH, et al. (1995)32P-Postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis, in press.

    Google Scholar 

  20. Fromson JM, Pearson S, Bramah S (1973) Metabolism of tamoxifen (ICI 46,474) Part II: In female patients. Xenobiotica 3:711–714.

    Article  PubMed  CAS  Google Scholar 

  21. Styles JA, Davies A, Lim CK, et al. (1994) Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis 15:5–9.

    Article  PubMed  CAS  Google Scholar 

  22. Mani C, Kupfer D (1991) Cytochrome P450 mediated action and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: Possible involvement of the flavin-containing monooxygenases in tamoxifen activation. Cancer Res 51:6052–6058.

    PubMed  CAS  Google Scholar 

  23. White INH, De Matteis F, Gibbs AH, et al. (1995) Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved. Biochem Pharmacol, in press.

    Google Scholar 

  24. Pathak DN, Pongracz K, Bodell WJ (1995) Microsomal and peroxidase activation of 4-hydroxytamoxifen to form DNA adducts: Comparison with DNA adducts formed in Sprague-Dawley rats treated with tamoxifen. Carcinogenesis 16:11–15.

    Article  PubMed  CAS  Google Scholar 

  25. Davies AM, Martin EA, Jones RM, et al. (1995) Peroxidase activation of tamoxifen and toremifene to cause DNA damage and covalently bound protein adducts. Carcinogenesis 16:539–545.

    Article  PubMed  CAS  Google Scholar 

  26. Phillips DH, Hewer A, White INH, et al. (1994) Co-chromatography of a tamoxifen epoxide-deoxyguanylic acid adduct with a major DNA adduct formed in the livers of tamoxifen-treated rats. Carcinogenesis 15:793–795.

    Article  PubMed  CAS  Google Scholar 

  27. Phillips DH, Potter GA, Horton MN, et al. (1994) Reduced genotoxicity of [D5-ethyl]-tamoxifen implicates a-hydroxylation of the ethyl group as a major pathway of tamoxifen activation to a liver carcinogen. Carcinogenesis 15:1487–1492.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Ian N. H. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lewis L. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Etiology and Prevention of Hormonal Cancers, Hormonal Carcinogenesis Laboratory, University of Kansas Cancer Center, Kansas City, Kansas, USA

    J. Jonathan Li Ph.D. (Professor of Pharmacology, Toxicology, and Therapeutics, Director) (Professor of Pharmacology, Toxicology, and Therapeutics, Director)

  2. Hormonal Carcinogenesis Laboratory, University of Kansas Cancer Center, Kansas City, Kansas, USA

    Sara Antonia Li Ph.D. (Associate Professor of Pharmacology, Toxicology, and Therapeutics) (Associate Professor of Pharmacology, Toxicology, and Therapeutics)

  3. Department of Medical Nutrition, Center for Biotechnology, NOVUM, Huddinge University Hospital, Huddinge, Sweden

    Jan-Åke Gustafsson M.D., Ph.D. (Professor and Chairman, Director) (Professor and Chairman, Director)

  4. Department of Molecular and Cell Biology, Cancer Research Center, University of California, Berkeley, California, USA

    Satyabrata Nandi Ph.D. (Professor of Cell and Development Biology) (Professor of Cell and Development Biology)

  5. Division of Cancer Etiology, Chemical and Physical Carcinogenesis Program, National Cancer Institute, Rockville, Maryland, USA

    Lea I. Sekely Ph.D. (Program Director) (Program Director)

  6. University of Kansas Medical Center, Kansas City, Kansas, USA

    J. Jonathan Li Ph.D. (Professor of Pharmacology, Toxicology, and Therapeutics, Director) & Sara Antonia Li Ph.D. (Associate Professor of Pharmacology, Toxicology, and Therapeutics) (Professor of Pharmacology, Toxicology, and Therapeutics, Director) &  (Associate Professor of Pharmacology, Toxicology, and Therapeutics)

  7. National Institutes of Health, Rockville, Maryland, USA

    Lea I. Sekely Ph.D. (Program Director) (Program Director)

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer-Verlag New York, Inc.

About this paper

Cite this paper

White, I.N.H., Smith, L.L. (1996). Mechanisms of Tamoxifen-Induced Genotoxicity and Carcinogenicity. In: Li, J.J., Li, S.A., Gustafsson, JÅ., Nandi, S., Sekely, L.I. (eds) Hormonal Carcinogenesis II. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-2332-0_26

Download citation

  • DOI: https://doi.org/10.1007/978-1-4612-2332-0_26

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4612-7506-0

  • Online ISBN: 978-1-4612-2332-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation