Abstract 178: Vitamin D reduces lung cancer progression the N-nitroso-tris-chloroethylurea model of mouse lung squamous cell carcinoma.

Abstract

Abstract Vitamin D, an essential mediator of calcium homeostasis, acts through the vitamin D receptor to promote cellular differentiation and inhibit proliferation. Epidemiologic studies indicate that low serum levels of 25(OH)D3 are associated with increased risk and poor prognosis of lung cancer. Pre-clinical studies in mice show that dietary vitamin D and calcium deficiency promote carcinogenesis in mouse models of cancer. These data suggest that vitamin D may have a role as a chemopreventive agent. To investigate the role of vitamin D in lung cancer, a carcinogen-induced model of lung squamous cell carcinoma (SCC) was employed. N-nitroso-tris-chloroethylurea (NTCU) was applied topically each week to the back of SWR/J mice. Following ∼15 weeks of NTCU treatment, mice on a standard diet begin to develop flat atypia, which progresses through dysplasia to invasive lung SCC by 35 to 40 weeks. We investigated the effects of vitamin D on cancer progression using different levels of dietary vitamin D3 and injections of the most active metabolite 1,25(OH)2D3 (calcitriol) in the NTCU model (80 mM/week). After 24 weeks of NTCU, mice on a deficient diet had more advanced disease than those on a sufficient diet. However, that study demonstrated that the 80 mM/week of NTCU was too toxic and resulted in premature death. A second vitamin D intervention study has now been completed using a less toxic dose of 40 mM/week of NTCU. In this study mice were randomized to 6 treatment groups (Table 1). Disease burden, as measured by histology (Table 1), was similar to that seen with higher dose NCTU. This study supports our earlier findings that vitamin D deficient mice develop disease at a more rapid rate when compared to mice that are sufficient. This also suggests that calcitriol administration may reduce the progression of lung SCC in mice that are vitamin D deficient. Further studies are on going to elucidate the mechanism by which vitamin D acts to slow the progression of lung SCC in this model. Table 1. Serum 25(OH)D3 levels & incidence of high-grade dysplasia and lung SCC. Group Carcinogen (NTCU) Diet Vitamin D (IU/kg) Serum 25(OH)D3 Level (ng/ml) High-grade Dysplasia (%) Lung SCC (%) D deficient − 0 <4 0/11 (0) 0/11 (0) D deficient +NTCU + 0 <4 13/13 (100) 11/13 (85) D deficient +NTCU & calcitriol (i.p. 80 ug/kg/w) + 0 <4 14/14 (100) 8/14 (57) D sufficient − 2,000 21 0/14 (0) 0/14 (0) D sufficient +NTCU + 2,000 19 13/14 (92) 4/14 (29) D sufficient +NTCU & calcitriol (i.p. 80 ug/kg/w) + 2,000 10 10/13 (76) 3/13 (20) Citation Format: Sarah A. Mazzilli, Mary Reid, Paul Bogner, Donald Trump, Candace Johnson. Vitamin D reduces lung cancer progression the N-nitroso-tris-chloroethylurea model of mouse lung squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 178. doi:10.1158/1538-7445.AM2013-178