Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1994 Jun;69(6):1171–1175. doi: 10.1038/bjc.1994.230

Combined treatment with 4-hydroxyandrostenedione and aminoglutethimide: effects on aromatase inhibition and oestrogen suppression.

F A MacNeill 1, S Jacobs 1, P E Lønning 1, T J Powles 1, M Dowsett 1
PMCID: PMC1969459  PMID: 8198987

Abstract

The effects of a combination of aminoglutethimide (AG) 1,000 mg daily and 4-hydroxy-androstenedione (4OHA) 500 mg i.m. weekly on peripheral aromatase activity as measured by in vivo radioisotopic tracer methodology and serum oestrogen suppression were investigated in ten post-menopausal women with advanced breast cancer. Patients were treated for a minimum of 4 weeks with 4OHA before addition of AG for a minimum of 6 weeks. Aromatase inhibition was found to be nearly identical in the two treatment situations (92.5 +/- 4.7% and 93.8 +/- 3.8% respectively). There was no further significant suppression of plasma oestradiol or plasma oestrone levels when AG was added to 4OHA treatment (mean decrease of 7.6 +/- 12.1% and 2.8 +/- 12.0% respectively). In contrast, adding AG caused a further suppression of plasma oestrone sulphate (Oe1S) compared with 4OHA monotherapy (mean suppression of 35.2 +/- 9.1%, P < 0.025). This effect on Oe1S may be due to an influence of AG on oestrogen metabolism.

Full text

PDF
1171

Selected References

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

  1. Dowsett M., Cunningham D. C., Stein R. C., Evans S., Dehennin L., Hedley A., Coombes R. C. Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res. 1989 Mar 1;49(5):1306–1312. [PubMed] [Google Scholar]
  2. Dowsett M., Goss P. E., Powles T. J., Hutchinson G., Brodie A. M., Jeffcoate S. L., Coombes R. C. Use of the aromatase inhibitor 4-hydroxyandrostenedione in postmenopausal breast cancer: optimization of therapeutic dose and route. Cancer Res. 1987 Apr 1;47(7):1957–1961. [PubMed] [Google Scholar]
  3. Dowsett M., Mehta A., King N., Smith I. E., Powles T. J., Stein R. C., Coombes R. C. An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients. Eur J Cancer. 1992;28(2-3):415–420. doi: 10.1016/s0959-8049(05)80065-6. [DOI] [PubMed] [Google Scholar]
  4. Dowsett M., Santner S. J., Santen R. J., Jeffcoate S. L., Smith I. E. Effective inhibition by low dose aminoglutethimide of peripheral aromatization in postmenopausal breast cancer patients. Br J Cancer. 1985 Jul;52(1):31–35. doi: 10.1038/bjc.1985.144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dowsett M., Stein R. C., Mehta A., Coombes R. C. Potency and selectivity of the non-steroidal aromatase inhibitor CGS 16949A in postmenopausal breast cancer patients. Clin Endocrinol (Oxf) 1990 May;32(5):623–634. doi: 10.1111/j.1365-2265.1990.tb00906.x. [DOI] [PubMed] [Google Scholar]
  6. Evans T. R., Di Salle E., Ornati G., Lassus M., Benedetti M. S., Pianezzola E., Coombes R. C. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res. 1992 Nov 1;52(21):5933–5939. [PubMed] [Google Scholar]
  7. Iveson T. J., Smith I. E., Ahern J., Smithers D. A., Trunet P. F., Dowsett M. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res. 1993 Jan 15;53(2):266–270. [PubMed] [Google Scholar]
  8. Jacobs S., Lønning P. E., Haynes B., Griggs L., Dowsett M. Measurement of aromatisation by a urine technique suitable for the evaluation of aromatase inhibitors in vivo. J Enzyme Inhib. 1991;4(4):315–325. doi: 10.3109/14756369109030396. [DOI] [PubMed] [Google Scholar]
  9. Johannessen D. C., Adlercreutz H., Fotsis T., Lønning P. E. Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione. Br J Cancer. 1993 Aug;68(2):393–398. doi: 10.1038/bjc.1993.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jones A. L., MacNeill F., Jacobs S., Lonning P. E., Dowsett M., Powles T. J. The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients. Eur J Cancer. 1992;28A(10):1712–1716. doi: 10.1016/0959-8049(92)90074-c. [DOI] [PubMed] [Google Scholar]
  11. Lien E. A., Anker G., Lønning P. E., Solheim E., Ueland P. M. Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res. 1990 Sep 15;50(18):5851–5857. [PubMed] [Google Scholar]
  12. Lipton A., Harvey H. A., Demers L. M., Hanagan J. R., Mulagha M. T., Kochak G. M., Fitzsimmons S., Sanders S. I., Santen R. J. A phase I trial of CGS 16949A. A new aromatase inhibitor. Cancer. 1990 Mar 15;65(6):1279–1285. doi: 10.1002/1097-0142(19900315)65:6<1279::aid-cncr2820650604>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  13. Lundgren S., Lønning P. E., Aakvaag A., Kvinnsland S. Influence of aminoglutethimide on the metabolism of medroxyprogesterone acetate and megestrol acetate in postmenopausal patients with advanced breast cancer. Cancer Chemother Pharmacol. 1990;27(2):101–105. doi: 10.1007/BF00689091. [DOI] [PubMed] [Google Scholar]
  14. Lønning E., Kvinnsland S., Bakke O. M. Effect of aminoglutethimide on antipyrine, theophylline, and digitoxin disposition in breast cancer. Clin Pharmacol Ther. 1984 Dec;36(6):796–802. doi: 10.1038/clpt.1984.259. [DOI] [PubMed] [Google Scholar]
  15. Lønning P. E., Dowsett M., Jones A., Ekse D., Jacobs S., McNeil F., Johannessen D. C., Powles T. J. Influence of aminoglutethimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione treatment. Breast Cancer Res Treat. 1992;23(1-2):57–62. doi: 10.1007/BF01831476. [DOI] [PubMed] [Google Scholar]
  16. Lønning P. E., Dowsett M., Powles T. J. Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer. J Steroid Biochem. 1990 Mar;35(3-4):355–366. doi: 10.1016/0022-4731(90)90241-j. [DOI] [PubMed] [Google Scholar]
  17. Lønning P. E., Jacobs S., Jones A., Haynes B., Powles T., Dowsett M. The influence of CGS 16949A on peripheral aromatisation in breast cancer patients. Br J Cancer. 1991 May;63(5):789–793. doi: 10.1038/bjc.1991.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lønning P. E., Johannessen D. C., Thorsen T. Alterations in the production rate and the metabolism of oestrone and oestrone sulphate in breast cancer patients treated with aminoglutethimide. Br J Cancer. 1989 Jul;60(1):107–111. doi: 10.1038/bjc.1989.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lønning P. E., Kvinnsland S. Mechanisms of action of aminoglutethimide as endocrine therapy of breast cancer. Drugs. 1988 Jun;35(6):685–710. doi: 10.2165/00003495-198835060-00005. [DOI] [PubMed] [Google Scholar]
  20. Lønning P. E., Kvinnsland S., Thorsen T., Ueland P. M. Alterations in the metabolism of oestrogens during treatment with aminoglutethimide in breast cancer patients. Preliminary findings. Clin Pharmacokinet. 1987 Dec;13(6):393–406. doi: 10.2165/00003088-198713060-00004. [DOI] [PubMed] [Google Scholar]
  21. Lønning P. E., Ueland P. M., Kvinnsland S. The influence of a graded dose schedule of aminoglutethimide on the disposition of the optical enantiomers of warfarin in patients with breast cancer. Cancer Chemother Pharmacol. 1986;17(2):177–181. doi: 10.1007/BF00306750. [DOI] [PubMed] [Google Scholar]
  22. MacNeill F. A., Jones A. L., Jacobs S., Lønning P. E., Powles T. J., Dowsett M. The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer. Br J Cancer. 1992 Oct;66(4):692–697. doi: 10.1038/bjc.1992.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Reed M. J., Lai L. C., Owen A. M., Singh A., Coldham N. G., Purohit A., Ghilchik M. W., Shaikh N. A., James V. H. Effect of treatment with 4-hydroxyandrostenedione on the peripheral conversion of androstenedione to estrone and in vitro tumor aromatase activity in postmenopausal women with breast cancer. Cancer Res. 1990 Jan 1;50(1):193–196. [PubMed] [Google Scholar]
  24. Santen R. J., Demers L. M., Adlercreutz H., Harvey H., Santner S., Sanders S., Lipton A. Inhibition of aromatase with CGS 16949A in postmenopausal women. J Clin Endocrinol Metab. 1989 Jan;68(1):99–106. doi: 10.1210/jcem-68-1-99. [DOI] [PubMed] [Google Scholar]
  25. Santen R. J., Santner S., Davis B., Veldhuis J., Samojlik E., Ruby E. Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J Clin Endocrinol Metab. 1978 Dec;47(6):1257–1265. doi: 10.1210/jcem-47-6-1257. [DOI] [PubMed] [Google Scholar]
  26. Santen R. J., Worgul T. J., Lipton A., Harvey H., Boucher A., Samojlik E., Wells S. A. Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med. 1982 Jan;96(1):94–101. doi: 10.7326/0003-4819-96-1-94. [DOI] [PubMed] [Google Scholar]
  27. Santner S. J., Feil P. D., Santen R. J. In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. J Clin Endocrinol Metab. 1984 Jul;59(1):29–33. doi: 10.1210/jcem-59-1-29. [DOI] [PubMed] [Google Scholar]
  28. Santner S. J., Rosen H., Osawa Y., Santen R. J. Additive effects of aminoglutethimide, testololactone, and 4-hydroxyandrostenedione as inhibitors of aromatase. J Steroid Biochem. 1984 Jun;20(6A):1239–1242. doi: 10.1016/0022-4731(84)90151-1. [DOI] [PubMed] [Google Scholar]
  29. Stein R. C., Dowsett M., Hedley A., Davenport J., Gazet J. C., Ford H. T., Coombes R. C. Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione. Cancer Chemother Pharmacol. 1990;26(1):75–78. doi: 10.1007/BF02940300. [DOI] [PubMed] [Google Scholar]
  30. Trunet P. F., Mueller P., Girard F., Aupetit B., Bhatnagar A. S., Zognbi F., Ezzet F., Menard J. The effects of fadrozole hydrochloride on aldosterone secretion in healthy male subjects. J Clin Endocrinol Metab. 1992 Mar;74(3):571–576. doi: 10.1210/jcem.74.3.1531483. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES