title: 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune responses.
abstract: The 20-epi-vitamin D3 analogues are a novel class of vitamin D3 derivatives, structurally related to 1 alpha,25-dihydroxycholecalciferol (1 alpha,25(OH)2D3). They are characterized by an altered stereochemistry at carbon 20 in the side-chain. In vitro, these new analogues were found to be considerably more potent as regulators of growth and differentiation in the human histiocytic lymphoma cell line U 937 than 1 alpha,25(OH)2D3, despite a practically unchanged calcemic activity in vivo. The most potent analogue, KH 1060, inhibited cell proliferation by 50% at 10(-12) M (14,000 times more active than 1 alpha,25(OH)2D3). At the same time, KH 1060 induced cell differentiation at concentrations as low as 10(-14)M. In addition, the 20-epi-vitamin D3 analogues were found to be very potent inhibitors of T-lymphocyte proliferation induced by interleukin-1 or alloantigen. In this respect, they were several orders of magnitude more active than the potent immunosuppressive agent cyclosporin A (CyA). KH 1060, the most potent analogue, inhibited interleukin-1-induced mouse thymocyte proliferation by 50% at 3 x 10(-16) M and allogeneic stimulation of mouse spleen lymphocytes at 5 x 10(15) M. These effects were considered to be mediated by inhibition of interleukin-2 release from activated T-lymphocytes. The new analogues are of potential interest in the prevention of graft rejection and in the treatment of psoriasis, cancer and auto-immune diseases.
authors.affiliation: Department of Biology, Leo Pharmaceutical Products, Ballerup, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Binderup
authors.forename: S
authors.initials: S
authors.lastname: Latini
authors.forename: E
authors.initials: E
authors.lastname: Binderup
authors.forename: C
authors.initials: C
authors.lastname: Bretting
authors.forename: M
authors.initials: M
authors.lastname: Calverley
authors.forename: K
authors.initials: K
authors.lastname: Hansen
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D016207:Cytokines; D011956:Receptors, Cell Surface; D016572:Cyclosporine; D002117:Calcitriol; D002118:Calcium