This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by ABE, J. Articles by IKEDA, K. Search for Related Content PubMed PubMed Citation Articles by ABE, J. Articles by IKEDA, K.

A Novel Vitamin D₃ Analog, 22-Oxa-1, 25- Dihydroxyvitamin D₃, Inhibits the Growth of Human Breast Cancer in Vitro and in Vivo without Causing Hypercalcemia^*

Research Laboratories, Chugai Pharmaceutical Co. Ltd. Tokyo 171
Fourth Department of Internal Medicine, University of Tokyo, Faculty of Medicine Tokyo 112, Japan

Address all correspondence and requests for reprints to: Kyoji Ikeda, M.D., Fourth Department of Internal Medicine, University of Tokyo, Faculty of Medicine, 3-28-6 Mejirodai, Bunkyo-ku, Tokyo 112, Japan.

Abstract

Although 1, 25-dihydroxyvitamin D₃ [1, 25- (OH)₂D₃] has been shown to inhibit the growth of certain malignant cells, its hypercalcemic effect has prevented clinical application. We have recently developed a novel vitamin D₃ analog, 22-oxa-1,25-(OH)₂D₃ (OCT), that is capable of promoting differentiation and inhibiting proliferation without inducing hypercalcemia. The present study was undertaken to determine whether OCT could be applied for the treatment of breast cancer with or without estrogen receptor (ER).

OCT inhibited the proliferation of both ER-positive (MCF-7, T-47D, and ZR-75-1) and ER-negative breast cancer cells (MDA-MB-231 and BT-20) in vitro in a time- and dose-dependent manner, as determined by cell number and [³H]thymidine uptake. The antiproliferative effect was observed with a concentration as low as 10^–11 M OCT, and treatment of MCF-7 cells with 10^–8 M OCT for 8 days caused more than a 50% reduction in cell number compared with that of vehicle-treated cells. OCT was approximately 1 order of magnitude more potent than 1,25-(OH)₂D₃ in inhibiting the proliferation of MCF-7 cells.

The in vivo effect of OCT was examined in athymic mice implanted with ER-negative MX-1 tumor, which was established as the xenograft derived from human breast carcinoma. Intratumor administration of OCT three times a week remarkably delayed the growth of MX-1 tumor in a time- and dose-dependent manner. The antitumor effect of 1 µg/kg BW OCT was greater than that of 500 µg/kg BW adriamycin, and the relative tumor weights in each group on day 26 were 29.7% and 50.5% of that in the vehicle-treated group, respectively. The effects of OCT and adriamycin were additive, and the relative tumor weight after 26 days of combined treatment was 21.7% of that in the vehicle-treated group. Oral administration of OCT was also effective, and the relative tumor weight in the OCT-treated group (1 µg/kg BW) was 54.6 ± 0.1% (mean ± SEM) of that in the vehicle-treated group. Neither intratumor nor oral administration of OCT raised the serum calcium level in these animals.

These results demonstrate that OCT is a potent inhibitor ot the proliferation of breast cancer cells with or without ER and that OCT inhibits the growth of breast cancer in vivo without inducing hypercalcemia. We suggest that OCT may provide a new strategy for the treatment of breast carcinoma regardless of ER status.

Footnotes

^* This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (to T.M.).

Received February 6, 1991.

This article has been cited by other articles:

				P. Dhawan, R. Weider, and S. Christakos CCAAT Enhancer-binding Protein {alpha} Is a Molecular Target of 1,25-Dihydroxyvitamin D3 in MCF-7 Breast Cancer Cells J. Biol. Chem., January 30, 2009; 284(5): 3086 - 3095. [Abstract] [Full Text] [PDF]

				K. Nakagawa, Y. Sasaki, S. Kato, N. Kubodera, and T. Okano 22-Oxa-1{alpha},25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer Carcinogenesis, June 1, 2005; 26(6): 1044 - 1054. [Abstract] [Full Text] [PDF]

				T. Kumagai, L.-Y. Shih, S. V. Hughes, J. C. Desmond, J. O'Kelly, M. Hewison, and H. P. Koeffler 19-Nor-1,25(OH)2D2 (a Novel, Noncalcemic Vitamin D Analogue), Combined with Arsenic Trioxide, Has Potent Antitumor Activity against Myeloid Leukemia Cancer Res., March 15, 2005; 65(6): 2488 - 2497. [Abstract] [Full Text] [PDF]

				A. Ismail, C. V. Nguyen, A. Ahene, J. C. Fleet, M. R. Uskokovic, and S. Peleg Effect of Cellular Environment on the Selective Activation of the Vitamin D Receptor by 1{alpha},25-Dihydroxyvitamin D3 and Its Analog 1{alpha}-Fluoro-16-Ene-20-Epi-23-Ene-26,27-Bishomo-25-Hydroxyvitamin D3 (Ro-26-9228) Mol. Endocrinol., April 1, 2004; 18(4): 874 - 887. [Abstract] [Full Text] [PDF]

				T. Kumagai, J. O'Kelly, J. W. Said, and H. P. Koeffler Vitamin D2 Analog 19-nor-1,25-Dihydroxyvitamin D2: Antitumor Activity Against Leukemia, Myeloma, and Colon Cancer Cells J Natl Cancer Inst, June 18, 2003; 95(12): 896 - 905. [Abstract] [Full Text] [PDF]

				M. Danilenko, X. Wang, and G. P. Studzinski Carnosic Acid and Promotion of Monocytic Differentiation of HL60-G Cells Initiated by Other Agents J Natl Cancer Inst, August 15, 2001; 93(16): 1224 - 1233. [Abstract] [Full Text] [PDF]

				K. S. Bramlett, Y. Wu, and T. P. Burris Ligands Specify Coactivator Nuclear Receptor (NR) Box Affinity for Estrogen Receptor Subtypes Mol. Endocrinol., June 1, 2001; 15(6): 909 - 922. [Abstract] [Full Text] [PDF]

				J.-i. Hisatake, J. O'Kelly, M. R. Uskokovic, S. Tomoyasu, and H. P. Koeffler Novel vitamin D3 analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells Blood, April 15, 2001; 97(8): 2427 - 2433. [Abstract] [Full Text] [PDF]

				C. M. Bula, J. E. Bishop, S. Ishizuka, and A. W. Norman 25-Dehydro-1{alpha}-Hydroxyvitamin D3- 26,23S-Lactone Antagonizes the Nuclear Vitamin D Receptor by Mediating a Unique Noncovalent Conformational Change Mol. Endocrinol., November 1, 2000; 14(11): 1788 - 1796. [Abstract] [Full Text]

				K. El Abdaimi, N. Dion, V. Papavasiliou, P.-E. Cardinal, L. Binderup, D. Goltzman, L.-G. Ste-Marie, and R. Kremer The Vitamin D Analogue EB 1089 Prevents Skeletal Metastasis and Prolongs Survival Time in Nude Mice Transplanted with Human Breast Cancer Cells Cancer Res., August 1, 2000; 60(16): 4412 - 4418. [Abstract] [Full Text]

				K. Koli and J. Keski-Oja 1{{alpha}},25-Dihydroxyvitamin D3 and Its Analogues Down-Regulate Cell Invasion-associated Proteases in Cultured Malignant Cells Cell Growth Differ., April 1, 2000; 11(4): 221 - 229. [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]

				H. Abe, N. Iehara, K. Utsunomiya, T. Kita, and T. Doi A Vitamin D Analog Regulates Mesangial Cell Smooth Muscle Phenotypes in a Transforming Growth Factor-beta Type II Receptor-mediated Manner J. Biol. Chem., July 23, 1999; 274(30): 20874 - 20878. [Abstract] [Full Text] [PDF]

				K. E. Abdaimi, V. Papavasiliou, S. A. Rabbani, J. S. Rhim, D. Goltzman, and R. Kremer Reversal of Hypercalcemia with the Vitamin D Analogue EB1089 in a Human Model of Squamous Cancer Cancer Res., July 1, 1999; 59(14): 3325 - 3328. [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]

				K.-I. Takeyama, Y. Masuhiro, H. Fuse, H. Endoh, A. Murayama, S. Kitanaka, M. Suzawa, J. Yanagisawa, and S. Kato Selective Interaction of Vitamin D Receptor with Transcriptional Coactivators by a Vitamin D Analog Mol. Cell. Biol., February 1, 1999; 19(2): 1049 - 1055. [Abstract] [Full Text] [PDF]

				N. Koike, N. Hayakawa, K. Kumaki, and W. E. Stumpf In Vivo Dose-related Receptor Binding of the Vitamin D Analogue [3H]-1,25-dihydroxy-22-oxavitamin D3 (OCT) in Rat Parathyroid, Kidney Distal and Proximal Tubules, Duodenum, and Skin, Studied by Quantitative Receptor Autoradiography J. Histochem. Cytochem., December 1, 1998; 46(12): 1351 - 1358. [Abstract] [Full Text]

				M. Falzon and J. Zong The Noncalcemic Vitamin D Analogs EB1089 and 22-Oxacalcitriol Suppress Serum-Induced Parathyroid Hormone-Related Peptide Gene Expression in a Lung Cancer Cell Line Endocrinology, March 1, 1998; 139(3): 1046 - 1053. [Abstract] [Full Text] [PDF]