Correlation between glucocorticoid receptor content and the antiproliferative effect of dexamethasone in experimental...

The present studies were conducted to assess the antiproliferative effects of dexamethasone (DEX) in murine, rat, and xenograft tumor models and to determine if this kinetic response could be correlated with the level of cytosolic glucocorticoid receptors. Saturable DEX receptors were determined by the dextran-coated charcoal competitive-binding assay, and the antiproliferative effects of DEX were determined by serial measurements of [3H]thymidine labeling indices before and after DEX treatments. The results from such studies in 3 colon tumor lines, one mouse (CO-38) and 2 human xenograft lines (LoVo, H81-4), were qualitatively similar. [3H]Thymidine labeling indices, initially reduced 50 to 60% by the DEX treatments, subsequently increased to as much as 2 times control values, 24 to 36 hr later. With the R3230AC rat mammary tumor model, the DEX dose-dependent antiproliferative effect was similar regardless of whether the tumor was grown in its syngeneic host, Fischer 344 rats, or as a xenograft in athymic nude mice. Studies using the B16 melanoma and SaD2 sarcoma tumor models indicated that the in vivo efficacy of vincristine, given after DEX, was highly sequence dependent. The results from these and other studies in glucocorticoid receptor-positive solid tumor models indicated that the DEX dose-dependent antiproliferative effect and the timing for maximal post-DEX [3H]thymidine labeling indices can be directly correlated with the level of saturable glucocorticoid receptors.