Growth inhibition of human colon adenocarcinoma-derived Caco-2 cells by 1,25-dihydroxyvitamin D3 and two synthetic analogs: relation to in vitro hypercalcemic potential.
The effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and of two synthetic analogs, 1,25S,26-tri-hydroxy-delta 22-vitamin D3 (1,25,26(OH)3-22ene-D3, Ro 23-4319) and 1,25-dihydroxy-delta 16-23yne-vitamin D3 (1,25(OH)2-16ene-23yne-D3, Ro 23-7553) on cell growth was evaluated by determination of [3H]thymidine incorporation into DNA of human colon adenocarcinoma-derived Caco-2 cells. The extent of growth inhibition by the vitamin D compounds varied between 20-40% (at 10(-8) M), depending on particular growth conditions of Caco-2 cells as well as on the molecular structure of the vitamin D sterols. In confluent, i.e., rather quiescent cells, all three vitamin D compounds were equipotent in suppressing growth. In rapidly dividing log phase cells, 1,25(OH)2-16ene-23yne-D3 or 1,25,26(OH)3-22ene-D3 were ten or five times, respectively, more efficient than 1,25(OH)2D3. A substantial effect on induction of the colonocyte differentiation marker alkaline phosphatase was only elicited by 1,25(OH)2-16ene-23yne-D3. The ability of the vitamin D compounds to raise intestinal calcium absorption was evaluated by determination of 45Ca2+ accumulation in embryonic chick duodenal explants. In this assay, both synthetic analogs were less effective than 1,25(OH)2D3 by a factor of 20. The intrinsic bone resorbing activities of the vitamin D analogs were compared in organ-cultured neonatal mouse calvariae. The most effective antiproliferative compound, 1,25(OH)2-16ene-23yene-D3, stimulated calcium release from cultured bones at concentrations less than 10(-11) M, and was thus ten times more potent than 1,25(OH)2D3 and hundred times more than 1,25,26(OH)3-22ene-D3.
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Department of General and Experimental Pathology, University of Vienna Medical School, Austria.
Farsoudi
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Peterlik
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D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000139:chemically induced; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D006887:Hydroxycholecalciferols / Q000494:pharmacology*; D006934:Hypercalcemia / Q000139:chemically induced / Q000503:physiopathology*; D007408:Intestinal Absorption / Q000187:drug effects; D051379:Mice; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006887:Hydroxycholecalciferols; C070643:1,24,26-trihydroxy-delta 22-vitamin D3; D002117:Calcitriol; C064183:Ro 23-7553; D002118:Calcium