GROWTH-INHIBITORY EFFECTS ON HUMAN COLON ADENOCARCINOMA-DERIVED CACO-2 CELLS AND CALCEMIC POTENTIAL OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 ANALOGS - STRUCTURE-FUNCTION-RELATIONSHIPS

A panel of synthetic analogs of 1 alpha,25-dihydroxyvitamin D-3 [1 alp ha,25(OH)(2)D-3] bearing one or multiple structural modifications at f unctionally or metabolically sensitive positions of the molecule, i.e. , C-1, 16, 23, 26 and 27, were tested for their growth inhibitory and prodifferentiating potency in human colon adenocarcinoma-derived Caco- 2 cells. With respect to the peak response elicited at 10(-8) M, 1 alp ha,25-dihydroxy-16-ene-vitamin D-3, 1 alpha,25-dihydroxy-23-yne-vitami n D-3 and 1 alpha,25-dihydroxy-16,23Z-diene-vitamin D-3 suppressed [H- 3]thymidine incorporation in confluent Caco-2 cells less than 1 alpha, 25(OH)(2)D-3, 1 alpha,25-dihydroxy-16,23e-diene-vitamin D-3 was at lea st equipotent to the parent compound, whereas 1 alpha,25-dihydroxy-16- ene-23-yne-vitamin D-3 and most conspicuously 1 5-dihydroxy-26,27-hexa fluoro-16-ene-23-yne-vitamin D-3 reduced growth of Caco-2 cells to sig nificantly (P < .05) lower levels than 1 alpha,25(OH)(2)D-3. The same rank order was obtained for the ability of the vitamin D compounds to induce activity of the differentiation marker enzyme, alkaline phospha tase, in quiescent Caco-2 cells. Whereas the effect of the synthetic a nalogs on calcium uptake by cultured embryonic chick duodenum in gener al was less pronounced than that of 1 alpha,25(OH)(2)D-3, the two most potent antimitogenic compounds, 1 alpha,25-dihydroxy-16-ene-23-yne-vi tam in D-3 and 1 5-dihydroxy-26,27-hexafluoro-16-ene-23-yne-vitamin D- 3, elicited calcium mobilization from cultured neonatal mouse calvaria at a 10-fold lower concentration than the parent compound, In additio n, these two synthetic analogs also were potent inducers of osteoclast -like cell differentiation in mouse bone marrow cultures, so that in v ivo a hypercalcemic effect of these vitamin D compounds at effective g rowth inhibitory dose levels must be considered possible. In contrast, 1 alpha,25-dihydroxy-16,23E-diene-vitamin D-3 matches if not exceeds 1 alpha,25(OH)(2)D-3 in its antiproliferative and prodifferentiating e fficacy in neoplastic colonic epithelial cells, but is a less potent i nducer of intestinal calcium transport and bone calcium mobilization.