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High Dose Vitamin D Study

ABSTRACT: The purpose of this study is to investigate the therapeutic effect and the safety of high-dose vitamin D supplementation in metastatic colorectal cancer patients. We propose to supplement metastatic (stage 4) colorectal cancer patients with oral doses of vitamin D to raise serum 25-hydroxy-vitamin D [25(OH)D] levels to the high normal range of 200-250 nmol/L. The primary objective of this study is to evaluate the metabolic consequences, including tolerability and toxicity, of prolonged, high-dose physiological vitamin D in patients with colorectal cancer. The secondary objective is to evaluate patient survival with regards to high-dose vitamin D supplementation. Hypothesis: Whereas low doses of vitamin D reportedly play a significant role in prevention of colorectal cancers, do much larger (pharmacological) doses of vitamin D have a significant therapeutic effect against the same kind of cancer?

DISEASE(S): Colon Cancer,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2091203 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:In order to understand the molecular mechanism responsible for the therapeutic potential of vitamin D, we conducted an analysis of the liver transcriptome – a central place of metabolic changes. The experiment was carried out on adult female rats (about one year old), n=18, divided into three experimental subjects, receiving different doses of vitamin D for three months: group I - 0, group II - 1000 U/Kg, group III - 5000 U/Kg. After the experiment, the biochemical and haematological parameters of the blood were evaluated. RNA-seq was used to analyze the changes in the liver transcriptome, and Gene Set Enrichment Analysis (GSEA) was used to identify enrichments in gene expression profiles of experimental groups. qPCR was employed to evaluate the expression of several genes connected to cholesterol biosynthesis, metallothioneins, vitamin D metabolism and others. At the end of the experiment, 25(OH) vitamin D concentrations were as follows: group I: 29 ng/ml, group II 43: ng/ml, group III: 70 ng/mL. Considering blood parameters, we observed a lower platelet count (p<0,008) and significantly higher (p<0.02) number of WBC in rats supplemented with 1000 U/Kg than in rats from group III (5000 U/Kg), but no difference between rats from group I and III were detected in these parameters. Moreover, we noted a trend (p<0.06 ) in total cholesterol concentration, suggesting a linear decrease with increasing doses of vitamin D. RNA-seq analysis did not identify any differentially expressed genes with FDR<0.05 in any of the three comparisons. However, GSEA revealed significant activation of the number of processes and pathways. In the I vs III comparison, the most enriched were the genes from the “metallothionein, and TspO/MBR family” (Enrichment Score=8,170, FDR= 0.00006), the genes associated with “glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity” (Enrichment Score=5.13, FDR<00049) and the genes associated with “Negative regulation of tumour necrosis factor production” (Enrichment score=1.26, FDR0.0064. qPCR analysis identified significant upregulation of Mt1, Mt2 and Orm1 genes in animals receiving high doses of vitamin D (p<0.025, p<0.025, p<0009, respectively). Moreover, significant downregulation of Srebp2 and Insig2 was observed in both experimental groups when compared to the control group (p<0.003, p<0.036, respectively). Our results support the potential of vitamin D supplementation in ameliorating oxidative stress, inflammation and high blood cholesterol and underlie the need for further studies aimed at identifying optimal vitamin D doses with therapeutic effects.

Project description:Background: Breast cancer patients present lower 1,25(OH)2D3 or 25(OH)D3 serum levels than unaffected women. Although 1,25(OH)2D3 pharmacological concentrations of 1,25(OH)2D3 may exert antiproliferative effects in breast cancer cell lines, much uncertainty remains about the effects of calcitriol supplementation in tumor specimens in vivo. We have evaluated tumor dimension (ultrassonography), proliferative index (Ki67 expression), 25(OH)D3 serum concentration and gene expression profile, before and after a short term calcitriol supplementation (dose to prevent osteoporosis) to post-menopausal patients. Results: Thirty three patients with operable disease had tumor samples evaluated. Most of them (87.5%) presented 25(OH)D3 insufficiency (<30 ng/mL). Median period of calcitriol supplementation was 30 days. Although tumor dimension did not vary, Ki67 immunoexpression decreased after supplementation. Transcriptional analysis of 15 matched pre/post-supplementation samples using U133 Plus 2.0 GeneChip (Affymetrix) revealed 18 genes over-expressed in post-supplementation tumors. As a technical validation procedure, expression of four genes was also determined by RT-qPCR and a direct correlation was observed between both methods (microarray vs PCR). To further explore the effects of near physiological concentrations of calcitriol on breast cancer samples, an ex vivo model of fresh tumor slices was utilized. Tumor samples from another 12 post-menopausal patients were sliced and treated in vitro with slightly high concentrations of calcitriol (0.5nM), that can be attained in vivo, for 24 hours In this model, expression of PBEF1, EGR1, ATF3, FOS and RGS1 was not induced after a short exposure to calcitriol. Conclusions: In our work, most post-menopausal breast cancer patients presented at least 25(OH)D3 insufficiency. In these patients, a short period of calcitriol supplementation may prevent tumor growth and reduce Ki67 expression, probably associated with discrete transcriptional changes. This observation deserves further investigation to better clarify calcitriol effects in tumor behavior under physiological conditions.

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High Dose Vitamin D Study

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