Epidemiologic, laboratory and clinical data suggest that vitamin D plays a favourable role in the prevention and prognosis of prostate cancer (PCa) and other malignancies. However, the metabolism and function of vitamin D in tissues beyond those involved in bone metabolism are poorly understood. The objective of this thesis was to investigate whether higher levels of vitamin D consumed orally or achieved in the circulation result in increased concentrations of vitamin D metabolites in human tissue, and how this affects cellular biology. The hallmark of this work is a randomized clinical trial of oral vitamin D3 (400-, 10,000-, or 40,000 IU/d) in PCa patients to evaluate the effects of supplementation on prostatic vitamin D metabolism and on PCa pathology. Various methods to measure vitamin D metabolites in serum were evaluated and modified to allow for measurement of these metabolites in tissue. Ultimately, I developed a robust tissue extraction method coupled to enzyme immunoassay and liquid chromatography-tandem mass spectrometry for measurement of calcitriol hormone, as well as 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D), respectively. Human colon tissue was analyzed first and found to contain calcitriol at physiologically relevant concentrations partly determined by serum calcitriol, with some evidence of local colonic synthesis. In the clinical trial, prostate tissue and serum levels of calcitriol, 25(OH)D and 24,25(OH)2D increased dose-dependently (p<0.02) without adverse side effects. The level of calcitriol attained in prostate tissue was inversely associated with the expression of Ki67 protein, a proliferation marker (p<0.05). Serum parathyroid hormone (PTH) and prostate specific antigen (PSA) declined from baseline in the combined higher-dose groups (10,000-40,000 IU/d) (p<0.02). We provide clinical trial evidence that prostatic vitamin D metabolism can be modulated in vivo by oral consumption of vitamin D3. Higher prostate calcitriol and vitamin D doses also showed suggestion of clinical benefit, including lowered Ki67 expression and modest reductions in serum PSA and PTH. Further studies are needed to validate the potential utility of dietary vitamin D3 supplementation in cancer prevention and therapy.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/65447 |
| Date | 19 June 2014 |
| Creators | Wagner, Dennis |
| Contributors | Vieth, Reinhold |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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