Abstract 1606: Antitumor effects of vitamin D in a carcinogen-induced mouse model of lung cancer

Abstract

Abstract Lung cancer accounts for the majority of cancer mortality in both men and women. It is critical to better understand the biology of lung cancer development as no preventive agents and few effective treatment options exist for lung cancer. Epidemiological studies indicate that low serum levels of 25(OH)D3 are associated with increased risk and poor prognosis of lung cancer. Calcitriol, the active metabolite of vitamin D, induces cell cycle arrest, apoptosis and differentiation in preclinical and clinical studies, has limited toxicity, and hence, is an attractive agent for chemoprevention. To investigate the preventive effects of vitamin D on lung squamous cell carcinoma (SCC), pre-clinical studies were conducted using a carcinogen-induced (CI) mouse model of lung SCC which uses N-nitroso-tris-chloroethylurea (NTCU) applied topically to the back of a SWR/J mouse twice weekly. Following ∼15 weeks of NTCU treatment, mice begin to develop bronchial epithelial hyperplasia and in time, progress through metaplasia, carcinoma in situ, and ultimately form lung SCC by approximately 35 to 40 weeks. We conducted a preliminary study investigating the effects of vitamin D on cancer progression in the CI model where animals received NTCU (80 mM/week). 12 week old female mice were randomized into one of three treatment groups: 1) vitamin D deficient diet (DD) (0IU D3 in the diet), 2) sufficient diet (SD) (2000IU/day D3 in the diet) and 3) SD with weekly intraperitoneal (IP) injections of calcitriol (80 ug/kg) (SD+D). Animals treated with NTCU on a DD, SD and SD+D had average serum 25(OH)D3 levels of 15, 70 and 75 nmol/L, respectively (normal range in mice is 70- 90 nmol/L). Preliminary histological evaluation at 12 weeks revealed bronchial epithelial hyperplasia in both the SD and SD+D groups. There were more advanced changes including hyperplasia, metaplasia and dysplasia in the DD mice. The histological evaluation of the DD mice at 24 weeks revealed even more advanced disease, in that most mice had developed lung SCC. The histological evaluation of the SD and SD+D groups at 24 weeks indicated the presence of bronchial epithelial hyperplasia, squamous metaplasia and dysplasia in all mice with some low level of carcinoma in situ. This study indicates that mice deficient in vitamin D develop disease at a more rapid rate suggesting that vitamin D status may play an important role in progression of lung SCC. Supported by NCCAM F31 AT006487 & R01-CA-067267. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1606. doi:1538-7445.AM2012-1606