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

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• 作者：Jan H. Beumer^a ; ^b ; Robert A. Parise^a ; ^b ; Beatriz Kanterewicz^c ; Martin Petkovich^d ; David Z. D&rsquo ; Argenio^e ; Pamela A. Hershberger^c ; ^f ; ^{Pamela.Hershberger@RoswellPark.org}
• 关键词：1 ; 25(OH)2D3 ; 1 ; 25-dihydroxyvitamin D3 ; FBS ; fetal bovine serum ; GUS ; 尾-glucuronidase ; LC&ndash ; MS/MS ; liquid chromatography&ndash ; tandem mass spectrometry ; PK ; pharmacokinetics ; qPCR ; quantitative PCR
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：April, 2012
• 卷：77
• 期：5
• 页码：477-483
• 文件大小：468 K

摘要

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 1.70 ng/mL, respectively, following intraperitoneal dosing (20 渭g/kg 1,25(OH)₂D₃). When co-administered with the CYP24 selective inhibitor CTA091 (250 渭g/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.