151. A local effect of CYP24 inhibition on lung tumor xenograft exposure to 1,25-dihydroxyvitamin D3 is revealed using a novel LC–MS/MS assay
- Author
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Beumer, Jan H., Parise, Robert A., Kanterewicz, Beatriz, Petkovich, Martin, D’Argenio, David Z., and Hershberger, Pamela A.
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CYTOCHROME P-450 , *LUNG tumors , *XENOGRAFTS , *THERAPEUTIC use of vitamin D , *LIQUID chromatography-mass spectrometry , *GENE expression - Abstract
Abstract: The vitamin D3 catabolizing enzyme, CYP24, is frequently over-expressed in tumors, where it may support proliferation by eliminating the growth suppressive effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). However, the impact of CYP24 expression in tumors or consequence of CYP24 inhibition on tumor levels of 1,25(OH)2D3 in vivo has not been studied due to the lack of a suitable quantitative method. To address this need, an LC–MS/MS assay that permits absolute quantitation of 1,25(OH)2D3 in plasma and tumor was developed. We applied this assay to the H292 lung tumor xenograft model: H292 cells eliminate 1,25(OH)2D3 by a CYP24-dependent process in vitro, and 1,25(OH)2D3 rapidly induces CYP24 expression in H292 cells in vivo. In tumor-bearing mice, plasma and tumor concentrations of 1,25(OH)2D3 reached a maximum of 21.6 and 1.70ng/mL, respectively, following intraperitoneal dosing (20μg/kg 1,25(OH)2D3). When co-administered with the CYP24 selective inhibitor CTA091 (250μg/kg), 1,25(OH)2D3 plasma levels increased 1.6-fold, and tumor levels increased 2.6-fold. The tumor/plasma ratio of 1,25(OH)2D3 AUC was increased 1.7-fold by CTA091, suggesting that the inhibitor increased the tumor concentrations of 1,25(OH)2D3 independent of its effects on plasma disposition. Compartmental modeling of 1,25(OH)2D3 concentration versus time data confirmed that: 1,25(OH)2D3 was eliminated from plasma and tumor; CTA091 reduced the elimination from both compartments; and that the effect of CTA091 on tumor exposure was greater than its effect on plasma. These results provide evidence that CYP24-expressing lung tumors eliminate 1,25(OH)2D3 by a CYP24-dependent process in vivo and that CTA091 administration represents a feasible approach to increase tumor exposure to 1,25(OH)2D3. [Copyright &y& Elsevier]
- Published
- 2012
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