Differentiating and antitumor activities of 1α,25‐dihydroxyvitamin D3 in vitro and 1α‐hydroxyvitamin D3 in vivo on human osteosarcoma

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Abstract
The differentiating and antitumor activities of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in vitro and 1α-hydroxyvitamin D3 (1α(OH)D3) in vivo were studied with a human osteosarcoma cell line (OST strain). Antitumor activity was estimated with the use of 3-(4,5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay, colony-forming assay, and athymic mouse assay. The intracellular alkaline phosphatase (ALP) activity of tumor cells and production of bone Gla protein (BGP) in culture media were measured to mark osteoblastic differentiation. In addition, the combination of 1α,25(OH)2D3 and cis-dichlorodiammineplatinum(II) (CDDP) was tested by the colony-forming assay and the measurement of ALP activity and BGP production for differentiating and antitumor effects. The assays revealed that 1α,25(OH)2D3 exerted a dose-related, growth-inhibitory influence. In the colony-forming assay, the 1α,25(OH)2D3-treated colonies were smaller than the untreated colonies. The ALP activity and the BGP production also increased in relation to dose. In the assay in athymic mice, the relative weight of tumors treated with 1α(OH)D3 at 2.5 nmol/kg was significantly smaller than that of the controls, and no side effects were observed in the 1α(OH)D3-treated mice. Marked tumor chondrogenesis was observed in human osteosarcoma treated with 1α(OH)D3 in athymic mice. The combination of 1α,25(OH)2D3 at 10−8 M and CDDP at 2 μg/ml significantly enhanced both the differentiation and the growth inhibition in vitro. Our study apparently is the first demonstration that vitamin D3 metabolites have an antitumor and differentiating effect on human osteosarcoma cells in vitro and in athymic mice. Vitamin D3 should be examined further to discover whether it could be a useful drug in hormonal treatment for human osteosarcomas.