Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihydroxyvitamin D3.
The use of 1,25-dihydroxyvitamin D3 as an antiproliferative agent in the treatment of cancer is limited by its hypercalcemic effects. Analogues with equivalent or greater antiproliferative activities but smaller hypercalcemic effects have been developed. The antiproliferative effects of 1,25-dihydroxyvitamin D3 and four analogues were studied in HT-29 and SW620 human colon cancer cell lines, moderate and low expressors of the vitamin D receptor, respectively. HT-29 is a primary, moderately differentiated, cell line, while SW620 is metastatic and poorly differentiated. Growth curve studies, proliferation assays, and clonogenic assays were used to assess the antiproliferative effects of 1,25-dihydroxyvitamin D3, 1,25-dihydroxy-16-ene-23-yne-D3, 1,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne-D3, 1,25-dihydroxy-16,23E-diene-26,27-hexafluoro-D3, and 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-D3. Growth of HT-29 cells was significantly inhibited by all four analogues at 10(-8) M (P < 0.05). Analogues 1,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne-D3, 1,25-dihydroxy-16,23E-diene-26,27-hexafluoro-D3, and 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-D3 were 2 times as potent as analogue 1,25-dihydroxy-16-ene-23-yne-D3 and 1,25-dihydroxyvitamin D3. SW620 cells did not show any growth inhibition with any of the compounds tested. The affinities of the three most potent analogues for the vitamin D receptor were similar to that of 1,25-dihydroxyvitamin D3, while that of analogue 1,25-dihydroxy-16-ene-23-yne-D3 was lower. These results demonstrate that, as in leukemic cells, analogues of 1,25-dihydroxyvitamin D3 are potent antiproliferative agents in colon cancer cells and this activity is most likely mediated through the vitamin D receptor.
Department of Surgery, Lombardi Cancer Research Center, Georgetown University Hospital, Washington, DC 20007.
M
M
Shabahang
R R
RR
Buras
F
F
Davoodi
L M
LM
Schumaker
R J
RJ
Nauta
M R
MR
Uskokovic
R V
RV
Brenner
S R
SR
Evans
D000469:Alkaline Phosphatase / Q000378:metabolism; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002272:Carcinoembryonic Antigen; D018167:Receptors, Calcitriol; D000469:Alkaline Phosphatase; D002117:Calcitriol