Growth inhibitory effects on human colon adenocarcinoma-derived Caco-2 cells and calcemic potential of 1 alpha,25-dihydroxyvitamin D3 analogs: structure-function relationships.
A panel of synthetic analogs of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] bearing one or multiple structural modifications at functionally 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 alpha,25-dihydroxy-16-ene-vitamin D3, 1 alpha,25-dihydroxy-23-yne-vitamin D3 and 1 alpha,25-dihydroxy-16,23Z-diene-vitamin D3 suppressed [3H]thymidine incorporation in confluent Caco-2 cells less than 1 alpha,25(OH)2D3. 1 alpha,25-dihydroxy-16,23e-diene-vitamin D3 was at least equipotent to the parent compound, whereas 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and most conspicuously 1 alpha,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne- vitamin D3 reduced growth of Caco-2 cells to significantly (P < .05) lower levels than 1 alpha,25(OH)2D3. The same rank order was obtained for the ability of the vitamin D compounds to induce activity of the differentiation marker enzyme, alkaline phosphatase, in quiescent Caco-2 cells. Whereas the effect of the synthetic analogs on calcium uptake by cultured embryonic chick duodenum in general was less pronounced than that of 1 alpha,25(OH)2D3, the two most potent antimitogenic compounds, 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and 1 alpha,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne-vitamin D3, elicited calcium mobilization from cultured neonatal mouse calvaria at a 10-fold lower concentration than the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)
Bischof
M G
MG
Department of General and Experimental Pathology, University of Vienna Medical School, Austria.
Redlich
K
K
Schiller
C
C
Chirayath
M V
MV
Uskokovic
M
M
Peterlik
M
M
Cross
H S
HS
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D018938:Caco-2 Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D004386:Duodenum / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002117:Calcitriol; D002118:Calcium