Skip to main content

Phase I Study of percutaneous 4-hydroxy-tamoxifen with analyses of 4-hydroxy-tamoxifen concentrations in breast cancer and normal breast tissue

Cancer Chemotherapy and Pharmacology volume 36, pages 493–498 (1995)Cite this article

Abstract

4-OH-tamoxifen is an active metabolite of tamoxifen that is detectable in the serum and tumour tissue of patients treated by oral tamoxifen. As this metabolite penetrates through the skin, it is possible to compare percutaneous 4-OH-tamoxifen (4-OH-TAM) and oral tamoxifen treatments. We report herein a randomized study of percutaneous 4-OH-TAM versus oral tamoxifen in women with breast cancer. This pharmacology study was designed to compare the 4-OH-TAM concentration in breast cancer and normal breast tissue according to the route and dose used for adminstration of tamoxifen after a 3-week period prior to surgery and tissue sampling. Women were randomized into one of the five following groups: group I, oral tamoxifen given at 10 mg twice a day; group II, 4-OH-TAM delivered percutaneously at 0.5 mg day to both breast areas; group III, 4-OH-TAM applied percutaneously at 1 mg/day to both breast areas; group IV, 4-OH-TAM delivered percutaneously at 1 mg/day to a large cutaneous area excluding the breasts; and group V, 4-OH-TAM applied percutaneously at 2 mg/day to a large skin area excluding the breasts. 4-OH-TAM plasma and tissue concentrations were significantly higher in the oral tamoxifen group as compared with either the high- or the low-dose percutaneous 4-OH-TAM group. In group II, percutaneous 4-OH-TAM treatment resulted in tissue concentrations of 1,446 and 352 pg/g in tumour tissue and normal breast tissue, respectively. In group I these concentrations were as follows: tumour tissue, 12, 453 pg/g; and normal tissue, 10,214 pg/g. 4-OH-TAM concentrations in tumour tissue and normal breast tissue did not significantly differ in any group. In the oral group we observed classic effects on coagulation and lipid metabolism when pre- and post-treatment values of these biological variables were compared, whereas no difference was observed in the percutaneous group. Although precutaneous administration of 4-OH-TAM led to a low plasmatic concentration of this active metabolite, the breast tissue concentration remained lower than those observed after oral tamoxifen treatment. Therefore, at the doses described in this study, percutaneous 4-OH-TAM cannot be proposed as an alternative tamoxifen treatment.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Bailar JC, Smith EM (1986) Progress against cancer? N Engl J Med 314: 1226–1232

    Google Scholar 

  2. Borgna JL, Rochefort H (1981) Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem 256: 859–868

    Google Scholar 

  3. Ching CK, Smith PG, Long RG (1992) Tamoxifen associated hepatocellular damage and agranulocytosis. Lancet 339: 940

    Google Scholar 

  4. Davidson NE (1992) Tamoxifen-panacea or Pandora's box? N Engl J Med 326: 885–886

    Google Scholar 

  5. Fisher B, Redmond C (1991) New perspective on cancer of the contralateral breast: a marker for assessing tamoxifen as a preventive agent. J Natl Cancer Inst 83: 1278–1280

    Google Scholar 

  6. Fisher B, Redmond C, Ford LG, Nayfield SG, Greenwald P (1992) Should healthy women take tamoxifen (letter)? N Engl J Med 26: 1596–1597

    Google Scholar 

  7. Fornander T, Rutqvist LE, Cedermark B, et al (1989) Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet II: 117–121

    Google Scholar 

  8. Fugh-Berman A, Epstein S (1992) Should healthy women take tamoxifen (letter)? N Engl J Med 26: 1596

    Google Scholar 

  9. Girault J, Istin B, Fourtillan JB (1993) Quantitative measurement of 4-hydroxy tamoxifen in human plasma and mammary tumours by combined gas chromatography/negative chemical ionization mass spectrometry. Biol Mass Spectrom 22: 395–402

    Google Scholar 

  10. Jordan VC (1992) Overview from the international conference on Long-Term Tamoxifen Therapy for Breast Cancer. J Natl Cancer Inst 84: 231–234

    Google Scholar 

  11. Love RR, Wiebe DA, Newcomb PA, et al (1991) Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115: 860–864

    Google Scholar 

  12. Love RR, Mazess RB, Barden HS, et al (1992) Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326: 852–856

    Google Scholar 

  13. Maudelonde T, Domergue J, Henquel C, et al (1989) Tamoxifen treatment increases the concentration of 52 K cathepsin D and its precursor in breast cancer tissue. Cancer 63: 1265–1270

    Google Scholar 

  14. Mauvais-Jarvis P, Baudot N, Castaigne D, Banzet P, Jutten F (1986) Trans-4-hydroxytamoxifen concentration and metabolism after local percutaneous administration to human breast. Cancer Res 46: 1521–1525

    Google Scholar 

  15. McDonald CC, Stewart HJ (1991) Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ 303: 435–437

    Google Scholar 

  16. Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS (1991) Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 83: 1450–1459

    Google Scholar 

  17. Neven, P, De Muylder X, Van Belle U, Vanderick G, De Muylder E (1989) Tamoxifen and the uterus and endometrium. Lancet I: 375

    Google Scholar 

  18. Pavlidis N, Petric C, Briassoulis E, et al (1992) Clear evidence that long-term low-dose tamoxifen treatment can induce ocular toxicity. Cancer 69: 2961–2964

    Google Scholar 

  19. Powles TJ (1992) The case for clinical trials of tamoxifen for prevention of breast cancer. Lancet 340: 1145–1147

    Google Scholar 

  20. Powles TJ, Hardy JR, Ashley SE, et al (1989) A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 60: 126–131

    Google Scholar 

  21. Powles TJ, Tillyer CR, Jones AL, et al (1990) Prevention of breast cancer with tamoxifen: and update on the Royal Marsden pilot programme. Eur J Cancer 26: 680–684

    Google Scholar 

  22. Rochefort H (1991) Mechanism of action of high-affinity antiestrogens. An overview. Am J Clin Oncol 14: S1-S4

    Google Scholar 

  23. Rochefort H, Maudelonde T (1989) Les antiostrogènes. Médecine/sciences Flammarion, Paris

    Google Scholar 

  24. Simony J, Pujol JL, Radal M, Ursule E, Michel FB, Pujol H (1990) In situ evaluation of growth fraction determined by monoclonal antibody Ki-67 and ploidy in surgically resected non-small cell lung cancers. Cancer Res 50: 4382–4387

    Google Scholar 

Download references

Author information

Affiliations

  1. Montpellier University Cancer Institute, F-34298, Montpellier Cedex, France

    Henri Pujol, Philippe Rouanet, Jean Grenier & Joëlle Simony

  2. Centre de Recherche CEMAF, 144 Rue de la Gibauderie, F-86000, Poitiers, France

    Jacques Girault & Jean-Bernard Fourtillan

  3. Besins Iscovesco Laboratories, 5, Rue du bourg de l'abbé, F-75003, Paris, France

    Sabine Fournier

  4. Hôpital Arnaud de Villeneuve, 555 Route de Ganges, F-34059, Montpellier Cedex, France

    Jean-Louis Pujol

Authors
  1. Henri Pujol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacques Girault
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philippe Rouanet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabine Fournier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean Grenier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joëlle Simony
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean-Bernard Fourtillan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Louis Pujol
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pujol, H., Girault, J., Rouanet, P. et al. Phase I Study of percutaneous 4-hydroxy-tamoxifen with analyses of 4-hydroxy-tamoxifen concentrations in breast cancer and normal breast tissue. Cancer Chemother. Pharmacol. 36, 493–498 (1995). https://doi.org/10.1007/BF00685799

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685799

Key words

  • Breast cancer
  • Chemoprevention
  • Pharmacology
  • Tamoxifen
  • Percutaneous administration