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Growth Suppression of Ovarian Cancer Xenografts in Nude Mice by Vitamin D Analogue EB1089

Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida

Requests for reprints: Wenlong Bai, Department of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 11, Tampa, FL 33612-4799. Phone: 813-974-0563; Fax: 813-974-5536; E-mail: wbai{at}hsc.usf.edu.

Purpose: The poor response of advanced epithelial ovarian cancer to current treatments necessitates the development of alternative therapeutic strategies. Inhibition of cancer growth by 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] compounds represents an innovative approach for cancer therapy. The current study evaluated the therapeutic potential of a synthetic 1,25(OH)₂D₃ analogue EB1089 in the treatment of ovarian cancer.

Experimental Design: The response of human ovarian cancer cells to 1,25(OH)₂D₃ and EB1089 were first compared in cell growth, gene transcription, and apoptotic assays. Then, nude mice bearing OVCAR3 tumor xenografts were treated with EB1089 at different dosages, and tumor volumes were monitored. The effect of EB1089 and 1,25(OH)₂D₃ on the level of serum calcium was also examined. After the treatment, tumors were excised and processed for histologic examination, Ki-67 staining, and tissue terminal deoxynucleotide transferase–mediated dUTP nick end labeling (TUNEL) assays to evaluate the morphologic, proliferative, and apoptotic changes induced by EB1089, respectively.

Results: The study shows that EB1089 suppresses the in vitro growth of ovarian cancer cells and transcriptionally activates the GADD45 reporter gene more effectively than 1,25(OH)₂D₃. Clinically more importantly, EB1089 suppresses the growth of OVCAR3 tumor xenografts in nude mice without inducing hypercalcemia. Ki-67 staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis contribute to the EB1089-induced tumor suppression in vivo.

Conclusions: This study is the first demonstration that ovarian cancer responds positively in vivo to treatment with a 1,25(OH)₂D₃ compound and thus supports continued development of 1,25(OH)₂D₃ analogues for possible use as an alternative or complementary therapy for human ovarian cancer.

Key Words: Apoptosis • 1,25(OH)₂D₃ • Nude mice • Proliferation • VDR

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