Abstract
Abstract Epidemiological data suggest that vitamin D3 deficiency plays a role in the pathogenesis and progression of human colorectal adenomas and adenocarcinomas. We have characterized the changes in plasma vitamin D3 metabolites (25-D3, 24,25-D3 and 1,25-D3), PTH and vitamin D3 binding protein (VDBP) levels, and peripheral blood mononuclear cells (PBMC) CYP24A1 activity in metastatic colorectal cancer (CRC) patients receiving 2000 IU of oral cholecalciferol daily over a 12 month period. Plasma samples were collected on day 0, 14, 30, 60, 90, 180, 270 and 360. Serum 25-D3 and 24,25-D3 were measured by LC/MS/MS method; plasma PTH and 1,25-D3 levels were determined by RIA. Plasma VDBP levels were measured by ELISA. PBMC CYP24A1activity was determined by HPLC method. A total of 50 CRC patients completed the study. Baseline 25-D3 were significantly influenced by season (p= 0.0145) . Baseline plasma 25-D3 levels were <30ng/mL in 66% of patients. Baseline plasma 24,25-D3, 1,25-D3 and VDBP levels were within the normal range. (The normal ranges are 0- 5ng/mL for 24,25-D3, 16 −80pg/mL for 1,25-D3 and 200 - 550μg/mL for VDBP). Mean baseline plasma PTH levels in patients with plasma 25-D3 <20ng/mL and >30ng/mL were 74.82 ± 27.02 and 56.46 ± 18.10pg/mL, respectively (p>0.05). Baseline PBMC CYP24A1activity was not affected by baseline 25-D3 levels. The increase in serum 25-D3 and 24,25-D3 levels during cholecalciferol treatment was characterized by an initial phase of rapid increase (between day 1 and day 90) followed by a phase of stable plasma 25-D3 and 24,25-D3 levels. A linear relation between plasma 25-D3 and 24,25-D3 was observed at baseline and during cholecalciferol supplementation (r2 = 0.55). No consistent changes in PBMC CYP24A1 activity was observed after 90 days of cholecalciferol treatment. The plasma 24,25-D3/25-D3 ratio at day 60 and 90 of cholecalciferol treatment was weakly correlated (r2=0.03 and 0.06, respectively) to changes in plasma 25-D3 levels. No CRC patient subsets with disproportional increase in plasma 24,25-D3 levels relative to 25-D3 levels during cholecalciferol treatment were identified suggesting that that variable 25-D3 responses cannot be explained by increased 24-hydroxylation. The increase in 1,25-D3 was linear, remained below 100pg/mL and did not correlate with plasma 25-D3 levels. A decrease in plasma PTH levels from 62.83 ± 24.84 to 41.61 ± 18.42 pg/mL was observed after 2 months of cholecalciferol supplementation (p<0.0001). Plasma VDBP protein levels were inconsistent across the study duration; no specific patterns or correlations with 25-D3 or 1,25-D3 could be identified. In summary, vitamin D3 deficiency, defined as 25-D3 <30 ng/mL, is prevalent in metastatic CRC patients. Furthermore, CYP24A1-mediated catabolism of 25-D3 to 24,25-D3 does not appear to be a major determinant of systemic 25-D3 levels. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 82.
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