Enhancement of 1,25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone

Background: The active metabolite of vitamin D, i.e., 1,25-dihydroxycholecalciferol (1,25-D-3), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D-3 is hampered as a result of hypercalcemia (i.e., elevated levels of calcium in the blood). Glucocorticoids, such as dexamethasone, affect calcium absorption and modulate vitamin D receptor binding and have been used to treat hypercalcemia. In this study, me examined the effect of dexamethasone on tumor growth inhibition by 1,25-D-3. Methods: The effects of 1,25-D-3 and dexamethasone, alone and in combination, on the growth of SCCVIL/SF cells in in vitro culture or in vivo in female C3H/HeJ mice were determined by clonogenic tumor cell assay and/or by actual changes in tumor volume. Vitamin D receptor-ligand-binding activities in whole-cell extracts from cells (in culture), tumors, and normal tissues were assayed by single-point saturation analysis and equilibrium binding, Results: Treatment of cultured SCCVII/SF cells with 500 nM dexamethasone for 24 hours before addition of 1,25-D-3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D-3 (as compared with no treatment or single-agent treatment); hypercalcemia was also reduced. Total vitamin D receptor content in SCCVII/SF cells was increased after treatment with dexamethasone, Treatment of tumor-bearing animals with dexamethasone (9 mug/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts item tumor or kidneys and decreased activity in intestinal mucosa, Conclusions: Dexamethasone may enhance the antitumor effect of 125-D-3 by increasing vitamin D receptor-ligand-binding activity.