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High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.

Ketoconazole, an antifungal agent, inhibits in vitro C17-C20 lyase, an enzyme involved in androgen biosynthesis. Since adrenal and ovarian androgens are the main precursors of oestrogens in postmenopausal women, the endocrine and therapeutic effects of high dose ketoconazole (400 mg three times a da...

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Autores principales: Harris, A. L., Cantwell, B. M., Dowsett, M.
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 1988
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246803/
https://www.ncbi.nlm.nih.gov/pubmed/2974717
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author Harris, A. L.
Cantwell, B. M.
Dowsett, M.
author_facet Harris, A. L.
Cantwell, B. M.
Dowsett, M.
author_sort Harris, A. L.
collection PubMed
description Ketoconazole, an antifungal agent, inhibits in vitro C17-C20 lyase, an enzyme involved in androgen biosynthesis. Since adrenal and ovarian androgens are the main precursors of oestrogens in postmenopausal women, the endocrine and therapeutic effects of high dose ketoconazole (400 mg three times a day) were evaluated in 14 postmenopausal women with advanced breast cancer. Testosterone levels were suppressed significantly (37%, P less than 0.025), as was dehydroepiandrosterone sulphate, and androstenedione levels showed a similar but non-significant fall. Seventeen hydroxyprogesterone levels rose significantly, as would be expected if C17-C20 lyase was inhibited. There was no suppression of cortisol or oestrone levels. There was a small suppression of oestradiol concentrations, reflecting a decrease in its precursor, testosterone. Sex hormone binding globulin levels rose, which may be due to a decrease in testosterone. All the changes are compatible with C17-C20 lyase as a major site of action in vivo. No responses occurred in 12 patients treated with ketoconazole alone, but in 2 patients who were progressing on aminoglutethimide, testosterone levels were suppressed and in one patient a partial response occurred. Ketoconazole was poorly tolerated due to gastrointestinal toxicity. This study shows that C17-C20 lyase is a potential target for hormone therapy, and that sequential blockade of enzymes involved in oestrogen biosynthesis should be further evaluated.
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spelling pubmed-22468032009-09-10 High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer. Harris, A. L. Cantwell, B. M. Dowsett, M. Br J Cancer Research Article Ketoconazole, an antifungal agent, inhibits in vitro C17-C20 lyase, an enzyme involved in androgen biosynthesis. Since adrenal and ovarian androgens are the main precursors of oestrogens in postmenopausal women, the endocrine and therapeutic effects of high dose ketoconazole (400 mg three times a day) were evaluated in 14 postmenopausal women with advanced breast cancer. Testosterone levels were suppressed significantly (37%, P less than 0.025), as was dehydroepiandrosterone sulphate, and androstenedione levels showed a similar but non-significant fall. Seventeen hydroxyprogesterone levels rose significantly, as would be expected if C17-C20 lyase was inhibited. There was no suppression of cortisol or oestrone levels. There was a small suppression of oestradiol concentrations, reflecting a decrease in its precursor, testosterone. Sex hormone binding globulin levels rose, which may be due to a decrease in testosterone. All the changes are compatible with C17-C20 lyase as a major site of action in vivo. No responses occurred in 12 patients treated with ketoconazole alone, but in 2 patients who were progressing on aminoglutethimide, testosterone levels were suppressed and in one patient a partial response occurred. Ketoconazole was poorly tolerated due to gastrointestinal toxicity. This study shows that C17-C20 lyase is a potential target for hormone therapy, and that sequential blockade of enzymes involved in oestrogen biosynthesis should be further evaluated. Nature Publishing Group 1988-10 /pmc/articles/PMC2246803/ /pubmed/2974717 Text en https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Harris, A. L.
Cantwell, B. M.
Dowsett, M.
High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
title High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
title_full High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
title_fullStr High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
title_full_unstemmed High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
title_short High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
title_sort high dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246803/
https://www.ncbi.nlm.nih.gov/pubmed/2974717
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