Abstract 2806: Effect of ED-71, an analogue of Vitamin D3, on intestinal neoplasia in the Apc+/Min-FCCC mouse model

Numerous studies have demonstrated an inverse relationship between circulating Vitamin D levels and risk of colorectal cancer. Although calcitriol, the most active form of Vitamin D3, exhibits promising antitumorigenic activity, its use as a chemopreventive agent has been restricted by its hypercalcemic effect at therapeutic doses. Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropyloxy) Vitamin D3 or ED-71), a novel analog of calcitriol, is more potent than calcitriol in stimulating bone modeling and is approved for the treatment of osteoporosis in Japan. The goal of the present study was to assess the activity of ED-71 against colorectal adenomas in a unique mouse model of spontaneous multiple intestinal neoplasia (Apc+/Min-FCCC mice). In a preliminary dose-finding study, male Apc+/Min-FCCC mice (6 weeks old, 6-7/group) were treated with vehicle (medium chain triglyceride (MCT)), calcitriol (0.25 μg/kg body weight (bw)), or ED-71 (0.2, 0.1, 0.05, 0.025, 0.0125 μg/kg bw) every other day by gavage for 6 weeks. Body weight was recorded weekly and mice were euthanized at the end of the study. ED-71 was well tolerated at all doses tested, with no significant difference in body weight observed in treated animals as compared to controls. Drug toxicity was assessed by measuring serum calcium levels by colorimetric assay (BioVision Inc.) and hepatic alkaline phosphatase (ALP) by ELISA (Antibodies-online.com). No significant effect of ED-71 on serum calcium levels and hepatic ALP activity was observed. However, because some concern exists regarding the ability of mice treated with high-dose ED-71 (0.2 μg/kg bw) to maintain their body weight long-term, ED-71 doses of 0.05 and 0.1 μg/kg bw were selected for the long-term efficacy study. Prior to entry on this study, male Apc+/Min-FCCC mice (6 weeks old) were prescreened endoscopically to determine tumor-bearing status. Mice were randomized based on tumor status (tumor-free or tumor-bearing) and body weight to one of four treatment groups: vehicle (MCT), calcitriol (0.25 μg/kg bw), ED-71 (0.05 μg/kg bw) or ED-71 (0.1 μg/kg bw). Drugs were administered by gavage every other day for 14 weeks. At the end of the study, intestinal tissue was examined grossly and tumor multiplicity was recorded. No significant effect of ED-71 on tumor multiplicity was observed in tumor-bearing mice. However, in tumor-free mice (11-13/group), treatment with ED-71 (0.1 μg/kg bw) reduced the incidence of gross tumors by 36% (P = 0.017) and colon tumor multiplicity by 30% as compared to that of controls (63.6% vs. 100%, 1.4 ± 0.4 vs. 2.0 ± 0.4, respectively). These findings suggest that ED-71 is effective in inhibiting colon tumorigenesis when given to mice prior to tumor formation. These promising data provide support for future studies to determine the potential utility of ED-71 for the prevention of colorectal cancer in high-risk subjects. (Supported by NCI HHSN261201200015I) Citation Format: Wen-Chi L. Chang, Esther Kaunga, Harry S. Cooper, Lisa Vanderveer, Jing Peng, Yongchao Zhang, Chen S. Suen, Margie L. Clapper. Effect of ED-71, an analogue of Vitamin D3, on intestinal neoplasia in the Apc+/Min-FCCC mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2015-2806