A local effect of CYP24 inhibition on lung tumor xenograft exposure to 1,25-dihydroxyvitamin D-3 is revealed using a novel LC-MS/MS assay

作者：Beumer Jan H; Parise Robert A; Kanterewicz Beatriz; Petkovich Martin; D' Argenio David Z; Hershberger Pamela A^*

来源：Steroids, 2012, 77(5): 477-483.

DOI：10.1016/j.steroids.2012.01.007

• Lung cancer
• CTA091
• CYP24
• 1,25-Dihydroxyvitamin D-3
• Pharmacokinetics

The vitamin D-3 catabolizing enzyme, CYP24, is frequently over-expressed in tumors, where it may support proliferation by eliminating the growth suppressive effects of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3). However, the impact of CYP24 expression in tumors or consequence of CYP24 inhibition on tumor levels of 1,25(OH)(2)D-3 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)(2)D-3 in plasma and tumor was developed. We applied this assay to the H292 lung tumor xenograft model: H292 cells eliminate 1,25(OH)(2)D-3 by a CYP24-dependent process in vitro, and 1,25(OH)(2)D-3 rapidly induces CYP24 expression in H292 cells in vivo. In tumor-bearing mice, plasma and tumor concentrations of 1,25(OH)(2)D-3 reached a maximum of 21.6 and 1.70 ng/mL, respectively, following intraperitoneal dosing (20 mu g/kg 1,25(OH)(2)D-3). When co-administered with the CYP24 selective inhibitor CTA091 (250 mu 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)(2)D-3 AUC was increased 1.7-fold by CTA091, suggesting that the inhibitor increased the tumor concentrations of 1,25(OH)(2)D-3 independent of its effects on plasma disposition. Compartmental modeling of 1,25(OH)(2)D-3 concentration versus time data confirmed that: 1,25(OH)(2)D-3 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)(2)D-3 by a CYP24-dependent process in vivo and that CTA091 administration represents a feasible approach to increase tumor exposure to 1.25(OH)(2)D-3.

• 出版日期2012-4