This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Norman, A. W. Articles by Koeffler, H. P. Search for Related Content PubMed PubMed Citation Articles by Norman, A. W. Articles by Koeffler, H. P.

Structure-Function Studies on Analogues of 1,25-Dihydroxyvitamin D₃: Differential Effects on Leukemic Cell Growth, Differentiation, and Intestinal Calcium Absorption¹

Division of Biomedical Sciences and Department of Biochemistry, University of California, Riverside, California 92521 [A. W. N.]; Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, California 90024 [J. Y. Z., H. P. K.]; Hoffmann-La Roche, Nutley, New Jersey 07110 [M. R. U.]; and Department of Biochemistry, University of California, Riverside, California 92521 [H. L. H.]

The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], is an efficient stimulator of intestinal calcium absorption (ICA) and bone calcium mobilization (BCM) in humans and experimental animals and, as well, has been shown to be effective in inducing differentiation and inhibiting proliferation of leukemia cells. Thus, it has been proposed that analogues of 1,25(OH)₂D₃ could be synthesized which might allow for separation of biological functions, i.e., promote a differentiation of leukemia cells without a significant stimulation of ICA or BCM, both biological effects which can cause hypercalcemia in humans. Here we report the results of an evaluation of four analogues of the previously studied (Zhou et al., Blood, 74:82–92, 1989) 1,25-dihydroxy-16-ene-23-yne-vitamin D₃ [1,25(OH)₂-16-ene-23-yne-D₃]; these analogues allowed evaluation of the consequences of (a) the presence or absence of six deuterium atoms on carbons 26 and 27 of the side chain and (b) the deletion or substitution by a fluorine atom of the 1-hydroxyl group on the A-ring.

The 1,25(OH)₂-16-ene-23-yne-D₃ analogue was found to be 7-fold more potent than the parent 1,25(OH)₂D₃ with respect to (a) inhibition of clonal proliferation of HL-60 cells as well as (b) induction of differentiation of HL-60 promyelocytes. Variants of this analogue which possessed the six deuterium atoms on carbons 26 and 27 were slightly less active than the 1,25(OH)₂-16-ene-yne-D₃. However, replacement of the 1-hydroxyl group by a 1-fluoro group, or the absence of the 1-hydroxyl group, resulted in analogues that were somewhat less effective than the parent 1,25(OH)₂D₃ in achieving these biological responses but more potent as inhibitors of the renal mitochondrial 25-OH-D₃-1-hydroxylase, the site of endogenous production of 1,25(OH)₂D₃. ICA and BCM were assessed in vivo in vitamin D-deficient chickens, and each of the analogues was markedly less potent than the standard 1,25(OH)₂D₃. The analogue 1,25(OH)₂-16-ene-23-yne-D₃ had 2% of the ICA and 3% of the BCM activity of the parent 1,25(OH)₂D₃. Absence of the 1-hydroxyl group or substitution of the 1-fluoro group for the 1-hydroxyl group significantly diminished both the ICA and BCM activity in comparison to 1,25(OH)₂-16-ene-23-yne-D₃. Receptor binding studies indicated that 1,25(OH)₂-16-ene-23-yne-D₃ competed about 75% as effectively as 1,25(OH)₂D₃ for 1,25(OH)₂D₃ receptors present in both chick intestinal cells and HL-60 cells.

In summary, the analogue of 1,25(OH)₂D₃ possessing a 16-ene-23-yne structure appears to be the most promising of several side chain analogues which have been studied relative to the possibility of providing a therapeutic benefit in leukemia/preleukemia; additionally, this analogue may prove to be useful in understanding the mechanism of action of vitamin D secosteroids in promoting cell differentiation.

¹ Supported in part by USPHS Grants CA-30512 and CA-43277. H. P. K. is a member of the Jonsson Comprehensive Cancer Center.

² To whom requests for reprints should be addressed, at Department of Biochemistry, University of California, Riverside, CA 92521.

Received 3/21/90. Accepted 8/ 2/90.

This article has been cited by other articles:

				J. Tan, P. P. Dwivedi, P. Anderson, B. K. Nutchey, P. O'Loughlin, H. A. Morris, B. K. May, A. Ferrante, and C. S. Hii Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity Mol. Cancer Ther., December 1, 2007; 6(12): 3131 - 3138. [Abstract] [Full Text] [PDF]

				T. Ikezoe, S. Gery, D. Yin, J. O'Kelly, L. Binderup, N. Lemp, H. Taguchi, and H. P. Koeffler CCAAT/Enhancer-Binding Protein {delta}: A Molecular Target of 1,25-Dihydroxyvitamin D3 in Androgen-Responsive Prostate Cancer LNCaP Cells Cancer Res., June 1, 2005; 65(11): 4762 - 4768. [Abstract] [Full Text] [PDF]

				M. Shiohara, M. Uskokovic, J. Hisatake, Y. Hisatake, K. Koike, A. Komiyama, and H. P. Koeffler 24-Oxo Metabolites of Vitamin D3 Analogues: Disassociation of Their Prominent Antileukemic Effects from Their Lack of Calcium Modulation Cancer Res., April 1, 2001; 61(8): 3361 - 3368. [Abstract] [Full Text]

				C. Crescioli, M. Maggi, G. B. Vannelli, M. Luconi, R. Salerno, T. Barni, M. Gulisano, G. Forti, and M. Serio Effect of a Vitamin D3 Analogue on Keratinocyte Growth Factor-Induced Cell Proliferation in Benign Prostate Hyperplasia J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2576 - 2583. [Abstract] [Full Text]

				J.-i. Hisatake, T. Kubota, Y. Hisatake, M. Uskokovic, S. Tomoyasu, and H. P. Koeffler 5,6-trans-16-ene-Vitamin D3: A New Class of Potent Inhibitors of Proliferation of Prostate, Breast, and Myeloid Leukemic Cells Cancer Res., August 1, 1999; 59(16): 4023 - 4029. [Abstract] [Full Text] [PDF]

				S. J. Sabet, S. R. Darjatmoko, M. J. Lindstrom, and D. M. Albert Antineoplastic Effect and Toxicity of 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 in Athymic Mice With Y-79 Human Retinoblastoma Tumors Arch Ophthalmol, March 1, 1999; 117(3): 365 - 370. [Abstract] [Full Text] [PDF]

				H. Asou, M. Koike, E. Elstner, M. Cambell, J. Le, M. R. Uskokovic, N. Kamada, and H. P. Koeffler 19-nor Vitamin-D Analogs: A New Class of Potent Inhibitors of Proliferation and Inducers of Differentiation of Human Myeloid Leukemia Cell Lines Blood, October 1, 1998; 92(7): 2441 - 2449. [Abstract] [Full Text] [PDF]

				M. J. Campbell, S. Park, M. R. Uskokovic, M. I. Dawson, and H. P. Koeffler Expression of Retinoic Acid Receptor-{beta} Sensitizes Prostate Cancer Cells to Growth Inhibition Mediated by Combinations of Retinoids and a 19-nor Hexafluoride Vitamin D3 Analog Endocrinology, April 1, 1998; 139(4): 1972 - 1980. [Abstract] [Full Text] [PDF]