Effects of 1 alpha,25-dihydroxyvitamin D3 and its analogs in cancer-associated hypercalcemia in vivo and in vitro, and in normal prostate epithelial and stromal primary cell cultures.

摘要

In recent years the active form of vitamin D, 1α,25-dihydroxyvitamin D₃, [1,25(OH)₂D₃] and its synthetic analogs have been shown to exert anti-tumor effects both in vitro and in vivo. However, most studies have been completed in human and rodent species with little information available in domestic species on the role of 1,25(OH)₂D₃ as an agent to influence tumor cell growth. The objectives of this study were to investigate effects of 1,25(OH)₂D₃ and its analogs on canine cancer associated hypercalcemia in vivo and in vitro and on primary cultures of normal canine prostatic epithelial and stromal cells.; In summary, our results showed that 1,25(OH)₂D₃-receptor (VDR) was present in canine adenocarcinoma (CAC-8) tumor, canine oral squamous cell carcinoma (SCC 2/88) cell line, and epithelium and stroma prostate gland and primary prostate cultures. 1,25(OH)₂D₃, EB1089, and analog V inhibited CAC-8 and SCC 2/88 cell growth and induced SCC 2/88 cell differentiation in a dose-dependent manner; however, they did not inhibit parathyroid hormone-related protein (PTHrP) production in both canine tumor cells. 1,25(OH)₂D₃ increased the expression of PTHrP mRNA and reduced the stimulatory effect of transforming growth factor-β (TGF-β) on PTHrP mRNA expression in SCC 2/88 cells.; In normal canine prostate, VDR and 1α-hydroxylase (1α-OHase) mRNA were present in both epithelium and stroma of prostate gland and the primary prostate cultures. VDR in epithelial cells appeared to be present at higher levels than in stromal cells by northern blot detection of VDR mRNA. 1,25(OH)₂D₃, 25(OH)₂D₃, and EB1089 inhibited epithelial cell growth in a dose-dependent manner. 1,25(OH) ₂D₃ and EB1089 stimulated stromal cell growth at 10 −7M. Prostatic epithelial cells treated with 1,25(OH)₂ D₃ and EB1089 had slightly increased VDR mRNA expression at 6 and 12 hours compared to vehicle-treated controls. There was no difference in the expression of 1α-OHase mRNA in both prostatic epithelial and stromal cells. 1,25(OH)₂D₃ and its analogs may be used effectively as antiproliferative agents for canine epithelial malignancies and normal prostatic epithelial cells.