Abstract 1968: Mutagenesis and carcinogenesis induced by dibenzo[a,l]pyrene in the mouse oral cavity: A potential new model for oral cancer

The annual incidence of cancer of the oral cavity and pharynx in the US is about 30,000 cases, similar to that for leukemia and pancreas, and resulting in a 5 yr survival rate of about 50%. Current models utilizing 4-nitroquinoline-N-oxide in rats and mice or 7,12-dimethylbenzanthracene in the hamster cheek pouch, suffer from relevancy of these synthetic carcinogens and/or the target site. One 2-year feeding study reported that dietary administration of the tobacco smoke carcinogen, benzo(a)pyrene (BaP) leads to tumors at several sites including tongue, but only at very high doses, and mainly in forestomach (Culp, S.J., et al., Carcinogenesis, 9, 117-124, 1998). Here as a potential new model, we investigated whether the more powerful tobacco smoke carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) is mutagenic and carcinogenic in the oral cavity of the B6C3F1 lacI and B6C3F1 mouse resp. upon topical application. Four groups of B6C3F1 lacI mice (6/group) received DB[a,l]P (12, 6, and 3 nmol) or vehicle 3x per week. B6C3F1 mice (20/group) received the same treatment, with an additional 24 nmol group. At 38 weeks the lacI mice were euthanized and DNA was isolated from tongue and upper oral mucosa. For the 12 nmol dose group, the mutant fraction (MF) in the cII gene in upper mucosa and tongue increased about 2-fold relative to that in vehicle-alone (5.2 +/- 0.8 and 4.6 +/- 1.2 vs 2.7 +/- 1.3 and 2.6 +/- 1.2) resp. in units of mutants/105 pfu. The increases were statistically significant (ρ = 0.023 and 0.016) for upper mucosa and tongue resp. The MF's at lower doses were non-significantly elevated. The mutational profile in the DB[a,l]P-induced mutants was compared with that induced by BaP in upper mucosa. BaP was previously shown to be mutagenic in many tissues including oral tissues when administered by gavage (Guttenplan, J.B, et al., Mutation Res., 559,199-210, 2004). Only 4% of BaP-induced mutations were at AT base pairs vs. 31% for DB[a,l]P; consistent with a report of the comparative mutational profile of BaP and DB[a,l]P in lung (Leavitt, S.A., et al., Mutagenesis 23, 445-450, 2008). The fraction of mutations at AT base pairs for DB[a,l]P is very similar to that observed in p53 mutations in the human oral cavity. One yr after the start of treatments, B6C3F1 mice were euthanized and oral squamous cell carcinomas (OSCC) were found in 31% of the high-dose group. Tumors were located in several sites in the oral cavity, although not in tongue. Immunohistochemical analyses revealed that p53 protein was overexpressed in malignant tissues, but not controls. The facts that DB[a,l]P induces mutations and tumors in the oral cavity, and has a mutational profile in oral tissue similar to that found in p53 in human OSCC, indicate DB[a,l]P administration to the mouse oral cavity will likely provide the basis for a new and more relevant model for cancer of the oral cavity than existing models. 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 1968.