© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 10, 745-753,
May 16, 2001
© 2001 Oxford University Press
Action of Low Calcemic 1
,25-Dihydroxyvitamin D3 Analogue EB1089 in Head and Neck Squamous Cell Carcinoma
Affiliations of authors: J. Prudencio, M. J. Black, Department of Otolaryngology–Head and Neck Surgery, Jewish General Hospital, Montreal, PQ, Canada; N. Akutsu, Y. Bastien, R. Lin, Department of Physiology, McGill University, Montreal; N. Benlimame, T. Wang, Montreal Centre for Experimental Therapeutics in Cancer and Lady Davis Institute for Medical Research, Montreal; M. A. Alaoui-Jamali, Department of Medicine, McGill University, Lady Davis Institute for Medical Research, and Montreal Centre for Experimental Therapeutics in Cancer; J. H. White, Departments of Physiology and Medicine, McGill University, and Montreal Centre for Experimental Therapeutics in Cancer.
Correspondence to: John H. White, Ph.D., Department of Physiology, McIntyre Medical Sciences Bldg., McGill University, 3655 Drummond St., Montreal, PQ, H3G 1Y6, Canada (e-mail: jwhite{at}med.mcgill.ca).
Background: 1
,25-Dihydroxyvitamin D3 [1,25(OH)2D3] and its analogues inhibit growth of various types of cancer cells. Although the therapeutic potential of 1,25(OH)2D3 is limited by its tendency to induce hypercalcemia, analogues such as EB1089 are potent inhibitors of cell growth and exhibit reduced calcemic effects. We analyzed the antiproliferative and calcemic effects of EB1089 in tissue culture and animal models of head and neck squamous cell carcinoma (SCC) to investigate its potential as a chemotherapeutic/chemopreventive agent. Methods: The effects of 1,25(OH)2D3 and EB1089 on cell growth and expression of p21WAF1/CIP1 and p27KIP1, which encode cyclin-dependent kinase inhibitors, and a novel target, gadd45, a growth-arrest and DNA-damage gene, were monitored in cultured murine AT-84 SCC cells. The effects of these agents on AT-84 cell growth in vitro and on growth of AT-84 tumors in syngeneic C3H mice were monitored; treatment started at the time of tumor implantation (early tumor model) or after 12 days (late tumor model). Weight and serum calcium levels were also monitored in these animals. All P values were two-sided. Results: Both 1,25(OH)2D3 and EB1089 arrested proliferation of AT-84 cells in G0/G1 phase, inhibited p21WAF1/CIP1 expression, and induced expression of p27KIP1 protein. 1,25(OH)2D3 also enhanced the expression of gadd45, apparently by a p53-independent mechanism. There was a statistically significant decrease in tumor growth for 1,25(OH)2D3-treated mice (P<.001 for early tumor model) and EB1089-treated mice (P<.001 and P = .001 for early and late tumor models, respectively). Unlike 1,25(OH)2D3, EB1089 did not induce cachexia or hypercalcemia. The effects of 1,25(OH)2D3 and EB1089 on expression of p21WAF1/CIP1 and GADD45 were similar in tumors and in vitro. Conclusions: EB1089 completely inhibited growth of AT-84 SCC cells at nanomolar concentrations, reduced tumor growth, and did not have calcemic effects. Our results support continued investigation of EB1089 as a chemopreventive/chemotherapeutic agent for head and neck SCC.
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