Abstract 2455: The fjord region (±)-anti-dibenzo[a,l]pyrene-11,12-dihydrodiol-13,14-epoxides ((±)-anti-DB[a,l]PDE), is a powerful and specific inducer of squamous cell carcinoma in the oral cavity of mice

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC), the sixth most common malignancy, represents a major international public health problem. The vast majority of HNSCC occurs in the oral cavity. Cancer of the mouth strikes about 30,000 Americans each year and less than 50% of patients survive 5 years after diagnosis. Tobacco and alcohol use are considered major causative agents. Current preclinical animal models to study oral carcinogenesis do not accurately mimic the biology of this disease in humans. We have developed a new mouse model by the application of the fjord region diol epoxide, (±)-anti-DB[a,l]PDE, a metabolite of the tobacco constituent dibenzo[a,l]pyrene (DB[a,l]P), to the oral cavity, and we showed for the first time that it is a powerful and specific inducer of oral squamous cell carcinoma (OSCC) in both tongue and oral tissues. Briefly, two groups of B6C3F1 mice (20/group) received doses of (±)-anti-DB[a,l]PDE (6, and 3 nmol) administered into the oral cavity; additional groups received the vehicle or left untreated as controls, 3 time a week for 38 weeks. Mice were sacrificed one year after the first carcinogen administration. The high dose induced 74 % and 100 % OSCC in the tongue and oral tissues, respectively; the corresponding values at the lower dose were 45 % and 89 %. Consistent with the carcinogenicity, we demonstrated powerful mutagenicity in CII gene in big blue mice and the mutation spectra in both tongue and oral tissues revealed similarity in the profiles between DB[a,l]PDE, and that of p53 mutations found in human OSCC. Using immunohistochemistry, we showed that (±)-anti-DB[a,l]PDE resulted in overexpression of p53 protein in malignant tissues compared to normal oral tissues and tongues. Collectively, we developed a non-surgical whole animal model which is the first to demonstrate the remarkable carcinogenicity and specificity of (±)-anti-DB[a,l]PDE in the oral cavity; this model is an appropriate platform for further exploring the genetic and epigenetic alterations that can truly account for the development of OSCC on humans. In addition, this model can be employed to study efficacies of novel cancer chemopreventive agents. Supported by NCI grant no. R01 CA 100924. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2455.