Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system

Objectives. Risk factors for prostate cancer (PCa)-related mortality include old age, black race, and residence in northern latitudes. The objectives of this study are to examine the in vitro and in vivo effects of 1,25-dihydroxycholecalciferol (1,25-D-3) and less-hypercalcemic analogues on the Dunning rat prostate adenocarcinoma model. Methods. To evaluate the effect of 1,25-D-3 on PCa in vitro, we used the highly metastatic Mat-lylu (MLL) and moderately metastatic R3327-AT-2 (AT-2) Dunning prostate cell lines, and examined effects on growth, clonogenicity, differentiation, and cell cycle. in vivo analysis included examination of the effects of these compounds on tumor growth and metastasis. Results. Using both the 3-day MTT and 7-day clonogenic assay, 1,25-D-3 demonstrated a growth inhibitory effect with a concentration for 50% inhibition (IC50) of approximately 20 mu M for both MLL and AT-2. Cell cycle analysis of treated MLL cells (10 mu M 1,25-D-3 for 48 hours) had 25% more cells in the G(0)/G(1) phase than did control cells. To examine the in vivo effect of 1,25-D-3 and the less hypercalcemic Vitamin D analogue, Ro25-6760 (or 6760), on MLL PCa growth and metastasis, tumors (5 x 10(5) cells) were implanted subcutaneously into the flank of Copenhagen rats on the same day that treatment was initiated with 1,25-D-3 (1 mu g) or 6760 (1 or 5 mu g); rats received treatment three times a week. After 3 weeks, 1,25-D-3 and 6760 (5 mu g dosing) resulted in an inhibition of tumor volume and a reduction in the number and size of lung metastases. Conclusions. These preclinical studies demonstrate the profound in vitro, or in vivo, or both antiproliferative and differentiating effects of 1,25-D-3 and 6760 on PCa and suggest that these drugs may have potential beneficial effects in the treatment of advanced PCa. (C) 1997, Elsevier Science Inc. All rights reserved.