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Potentiating inhibitory effects of the non-1α-hydroxylated precursor vitamin D analogue of EB1089 (EB1285) and ketoconazole in parathyroid cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
(English)Article in journal (Refereed) Submitted
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93563OAI: oai:DiVA.org:uu-93563DiVA: diva2:167083
Available from: 2005-10-17 Created: 2005-10-17 Last updated: 2016-04-28
In thesis
1. Vitamin D Hydroxylating Enzymes and Analogues in Parathyroid Tumors and Breast Cancer
Open this publication in new window or tab >>Vitamin D Hydroxylating Enzymes and Analogues in Parathyroid Tumors and Breast Cancer
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In hyperparathyroidism (HPT) raised serum concentrations of ionized calcium is caused by increased secretion of parathyroid hormone (PTH) by parathyroid tumors. Active vitamin D, 1α,25-dihydroxyvitamin D3, is known to suppress PTH secretion and to reduce proliferation of parathyroid tumor cells.

The aim of this thesis was to examine expression of vitamin D hydroxylating enzymes, regulating the activation and inactivation of vitamin D and to study effects of vitamin D analogues, in parathyroid tumors and breast cancer.

The vitamin D activating enzyme, CYP27B1/25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase) and the vitamin D inactivating enzyme CYP24A1/25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) were expressed in parathyroid tumors and breast cancer.

The parathyroid tumors had raised expression levels of 1α-hydroxylase and reduced levels of 24-hydroxylase in comparison to normal parathyroid glands, indicating ability for endogenous activation of vitamin D. The expression of 1α-hydroxylase may be of therapeutic advantage for local activation of non-1α-hydroxylated vitamin D analogues in tumor cells, thereby reducing unwanted hypercalcemic effects.

Three of five selected low calcemic vitamin D analogues had as efficient PTH suppressing effect, in bovine parathyroid cells, as three vitamin D analogues used clinically for treatment of secondary HPT.

The non-1α-hydroxylated vitamin D analogue EB1285 showed antiproliferative and PTH suppressive effects as well as transcriptional activity in parathyroid and breast tumor cells, respectively.

Ketoconazole, an inhibitor of vitamin D hydroxylating enzymes, suppressed PTH secretion and potentiated the effect of vitamin D analogues. Combined treatment with vitamin D analogues and specific 24-hydroxylase inhibitors may be important for future therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 78
Keyword
Surgery, hyperparathyroidism, breast cancer, vitamin D, CYP27B1, CYP24A1, vitamin D analogues, ketoconazole, vitamin D receptor, Kirurgi
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-6008 (URN)91-554-6361-4 (ISBN)
Public defence
2005-11-08, Rosénsalen, Kvinnokliniken, Akademiska sjukhuset ing 95, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-10-17 Created: 2005-10-17Bibliographically approved

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Segersten, UlrikaHellman, PerÅkerström, GöranWestin, Gunnar

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