We hypothesized that 1,25-dihydroxyvitamin D3 (1,25D3) and its analogues may inhibit acute myelogenous leukemia (AML) proliferation by interrupting IL-1beta-mediated growth-stimulatory signals. The incubation of the IL-1beta- responsive AML cell line OCIM2 with 10 nM 1,25D3 reduced growth 80% in liquid culture, and a 100-1000-fold lower concentration of 20-epi analogues (MC1288 and MC1301) was sufficient to achieve similar growth inhibition. The growth inhibition was associated with a rapid but transient downregulation of IL-1beta and IL-1beta-converting enzyme (ICE) mRNAs in 1,25D3- and 20-epi analogue- treated cells, and the 20-epi analogue was more effective than 1,25D3 in repressing ICE expression. An examination of long-term changes in the levels of mature IL-1beta and its precursor revealed that 24-h incubation of OCIM2 with either 1,25D3 or its 20-epi analogues abolished the production of mature IL-1beta. The effect of 1,25D3 and its analogues on growth of fresh bone marrow cells from seven AML patients was tested by a clonogenic assay. Growth inhibition of 60% was reached in only one of seven 1,25D3-treated samples, but all seven samples were inhibited 60-90% by the 20-epi analogue MC1301. Growth inhibition by 1,25D3 and the analogue was reversible by addition of IL-1beta. These results suggest that 1,25D3 and its 20-epi analogues interrupt IL-1beta autocrine growth regulation by inhibiting IL-1beta production and processing but not the response to IL-1beta.

1997-03-01·British journal of pharmacology2区 · 医学

Effects of 1,25‐dihydroxyvitamin D₃ and its 20‐epi analogues (MC 1288, MC 1301, KH 1060), on clonal keratinocyte growth: evidence for differentiation of keratinocyte stem cells and analysis of the modulatory effects of cytokines

2区 · 医学

Article

作者: Gniadecki, R

Keratinocytes are functionally divided into stem cells, transit amplifying cells and terminally differentiated cells. In a hyperproliferative skin disease, psoriasis, increased mitotic activity of the stem cells is chiefly responsible for epidermal hyperplasia. The effects of 1,25dihydroxyvitamin D3 (1,25(OH)2D3) and potent vitamin D3 analogues (MC 1288: 20‐epi‐1,25(OH)2D3, MC 1301: 20‐epi‐24a‐homo‐26,27‐dimethyl‐1,25(OH)2D3, KH 1060: 20‐epi‐22‐oxa‐24a‐homo‐26,27‐dimethyl‐1,25(OH)2D3) on the stem cells were investigated.Stem cells were identified retrospectively as those giving rise to large keratinocyte colonies in culture (holoclones). 1,25(OH)2D3 (10−8–10−6m) suppressed formation of holoclones by stimulating the progenitor cell differentiation into the phenotype expressing differentiation markers (keratins K1/K10 and involucrin).20‐Epi vitamin D3 analogues were more potent than 1,25(OH)2D3 in inhibiting the clonal keratinocyte growth. This activity correlated with the ability to induce cell differentiation (KH 1060>MC 1301>MC 1288>1,25(OH)2D3).Cytokines modulated the effects of 1,25(OH)2D3 on clonal growth. One of the following cytokines (epidermal growth factor, transforming growth factor α, interleukin‐1α, interleukin‐1β, interleukin‐6, interleukin‐8) was required for 1,25(OH)2D3 to suppress clonal growth and induce cell differentiation. In contrast, keratinocyte growth factor and insulin‐like growth factor I attenuated the effects of 1,25(OH)2D3.In conclusion, 1,25(OH)2D3 and 20‐epi vitamin D3 analogues suppress clonal growth by directly inducing the differentiation of progenitor cells. It is conceivable that stimulation of stem cells differentiation is a major mechanism of action of vitamin D3 compounds in psoriasis. Balance between different types of cytokines in psoriatic epidermis may be an important factor determining the clinical effect of vitamin D‐based therapy.British Journal of Pharmacology (1997) 120, 1119–1127; doi:10.1038/sj.bjp.0701015

1995-03-01·Biochemical pharmacology2区 · 医学

Stimulation of epidermal proliferation in mice with 1α,25-dihydroxyvitamin D3 and receptor-active 20-epi analogues of 1α,25-dihydroxyvitamin D3

2区 · 医学

Article

作者: Serup, Joergen ; Gniadecki, Robert

The effects of 1 alpha, 25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) and receptor-active 20-epi vitamin D analogues (MC 1288, 20-epi-1 alpha, 25-(OH)2D3; MC 1301, 20-epi-24a-homo-26,27-dimethyl-1 alpha, 25-(OH)2D3, and KH 1060: 20-epi-22-oxa-24a-homo-26,27-dimethyl-1 alpha, 25-(OH)2D3) on epidermal proliferation in mice were studied in vivo. Single topical applications of all compounds induced epidermal proliferation in a dose-dependent manner. The relative potencies in vivo (KH 1060 > MC1301 > MC1288 > 1 alpha, 25-(OH)2D3) correlated well with the known activities of these compounds to inhibit U 937 cell proliferation in vitro. Vitamin D3 and 1 beta, 25-(OH)2D3, two compounds that do not bind the vitamin D receptor, did not affect epidermal proliferation. Our study shows that vitamin D3 compounds that bind to the vitamin D receptor stimulate epidermal proliferation in mice.

100 项与 MC-1301 相关的药物交易

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