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-D3), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D3 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, we examined the effect of dexamethasone on tumor growth inhibition by 1,25-D3.


METHODS
The effects of 1,25-D3 and dexamethasone, alone and in combination, on the growth of SCCVII/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-D3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D3 (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 microg/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa.


CONCLUSIONS
Dexamethasone may enhance the antitumor effect of 1,25-D3 by increasing vitamin D receptor-ligand-binding activity.
Yu
W D
WD
Department of Otolaryngology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, PA 15213, USA.
McElwain
M C
MC
Modzelewski
R A
RA
Russell
D M
DM
Smith
D C
DC
Trump
D L
DL
Johnson
C S
CS
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002117:Calcitriol / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018167:Receptors, Calcitriol / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D018167:Receptors, Calcitriol; D003907:Dexamethasone; D002117:Calcitriol