© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 12, 896-905,
June 18, 2003
© 2003 Oxford University Press
ARTICLE |
Vitamin D2 Analog 19-nor-1,25-Dihydroxyvitamin D2: Antitumor Activity Against Leukemia, Myeloma, and Colon Cancer Cells
Affiliation of authors: T. Kumagai, J. O’Kelly, H. P. Koeffler (Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center), J. W. Said (Department of Pathology, Center for Health Science), University of California at Los Angeles School of Medicine, Los Angeles, CA.
Correspondence to: Takashi Kumagai, M.D., Cedars-Sinai Medical Center/UCLA, School of Medicine, Davis Bldg. 5068, 8700 Beverly Blvd., Los Angeles, CA 90048 (e-mail: kumamed1_2001{at}yahoo.co.jp).
Background: 1,25-Dihydroxyvitamin D3 inhibits growth of several types of human cancer cells in vitro, but its therapeutic use is hampered because it causes hypercalcemia. 19-nor-1,25-Dihydroxyvitamin D2 (paricalcitol) is a noncalcemic vitamin D analog that is approved by the Food and Drug Administration for the treatment of secondary hyperparathyroidism. We investigated the antitumor activity and mechanism of action of paricalcitol in vitro and in vivo. Methods: Effects of paricalcitol on proliferation, the cell cycle, differentiation, and apoptosis were examined in cancer cell lines. Effects on tumor growth were examined with colon cancer cell xenografts in nude mice (five in the experimental group and five in the control group). The interaction of paricalcitol with the vitamin D receptor (VDR) in mononuclear spleen cells and myeloid stem cells from wild-type and VDR knockout mice was examined. All statistical tests were two-sided. Results: Paricalcitol inhibited the proliferation of myeloid leukemia cell lines HL-60, NB-4, and THP-1 cells at an effective dose that inhibited growth 50% (ED50) of 2.4–5.8 x 10-9 M by inducing cell cycle arrest and differentiation. Paricalcitol inhibited the proliferation of NCI-H929 myeloma cells at an ED50 of 2.0 x 10-10 M by inducing cell cycle arrest and apoptosis. Paricalcitol also inhibited the proliferation of colon cancer cell lines HT-29 (ED50 = 1.7 x 10-8 M) and SW837 (ED50 = 3.2 x 10-8 M). HT-29 colon cancer xenografts in paricalcitol-treated nude mice were smaller (1044 mm3 and 1752 mm3, difference = 708 mm3, 95% confidence interval = 311 to 1104 mm3; P = .03) and weighed less (1487 mg and 4162 mg, difference = 2675 mg, 95% confidence interval = 2103 to 3248 mg; P<.001) than those in vehicle-treated mice. Paricalcitol induced committed myeloid hematopoietic stem cells from wild-type but not from VDR knockout mice to differentiate as macrophages. Conclusion: Paricalcitol has anticancer activity against myeloid leukemia, myeloma, and colon cancer cells that may be mediated through the VDR. Because it has been approved by the Food and Drug Administration, clinical trials of this agent in certain cancers are reasonable.
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