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Growth Inhibition of HT-29 Human Colon Cancer Cells by Analogues of 1,25-Dihydroxyvitamin D₃

Department of Surgery, Lombardi Cancer Research Center, Georgetown University Hospital, Washington DC 20007 [M. S., R. R. B., F. D., L. M. S., R. J. N., R. V. B., S. R. T. E.], and Hoffman-La Roche Company, Nutley, New Jersey 07110 [M. R. U.]

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.

¹ To whom requests for reprints should be addressed, at Department of Surgery, 4PHC, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington DC 20007.

Received 1/31/94. Accepted 5/23/94.

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