INHIBITION OF BREAST-CANCER CELL-GROWTH BY COMBINED TREATMENT WITH VITAMIN-D-3 ANALOGS AND TAMOXIFEN

The steroid hormone 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] has po tential to be used as an antitumor agent, but its clinical application is restricted by the strong calcemic activity. Therefore, new vitamin D-3 analogues are developed with increased growth inhibitory and redu ced calcemic activity. Tn the present study, we have examined the anti proliferative effects of four novel vitamin D-3 analogues (CB966, EB10 89, KH1060, and 22-oxa-calcitriol) on breast cancer cells, either alon e or in combination with the antiestrogen tamoxifen. The estrogen-depe ndent ZR-75-1 and estrogen-responsive MCF-7 cell lines were used as a model. It was shown that, with EB1089 and KH1060, the same growth inhi bitory effect as 1,25-(OH)(2)D-3 could he reached at up to 100-fold lo wer concentrations, whereas CB966 and 22-oxa-calcitriol were nearly eq uipotent with 1,25-(OH)(2)D-3. The growth inhibition by the vitamin D- 3 compounds could be augmented by combined treatment with tamoxifen. A t the maximal effective concentrations of the vitamin D-3 compounds, t he effect of combined treatment was additive (MCF-7 cells) or less tha n additive (ZR-75-1 cells). Tamoxifen increased the sensitivity of the cells to the vitamin D-3 compounds 2- to 4000-fold, which was express ed by a shift to lower median effective concentration values. Thereby, the vitamin D-3 compounds may be used at even lower dosages in combin ation therapy with tamoxifen. A major problem of tamoxifen therapy is the development of tamoxifen resistance. We have observed that tamoxif en-resistant clones of ZR-75-1 cells retain their response to the vita min D-3 compounds. Regulation of the growth-related oncogene c-myc (mR NA level) and the estrogen receptor (protein level) were studied but a ppeared not to be related to the antiproliferative action of the vitam in D-3 compounds. Together, our data point to a potential benefit of c ombination therapy with 1,25-(OH)(2)D-3 or vitamin D-3 analogues and t amoxifen for the treatment of breast cancer.