Tobacco Derived Carcinogen Induced Early Oral Cancer Markers

There is a link between tobacco derived carcinogens and oral cancer. Objective: Markers are needed for early detection and prevention of oral cancer, and to monitor treatments to reduce mortality. We studied early markers during the course of Syrian hamster oral carcinogenesis in the tongue(T) and floor of mouth(FOM) induced by tobacco carcinogen application. Methods:Dissolved in acetone, benzo[a]pyrene (1.25 uM/application) and dibenz[a,l]pyrene(DB[a,l]P, (0.010 uM)were applied to T and FOM. Tumor incidence and marker expressions were compared to non-treated controls in 25 animals/group after 35 weeks. Oral cytology (OC) samples were taken from the T/FOM starting week 1 and every third week for 30 weeks.OC samples were automated stained for immunohistochemistry(“Discovery”, Ventana), laser scanned cytometry detected(“iCys”LSC, Compucyte)and analyzed using “ModFit” cell cycle software. Results: DB[a,l]P produced more tumor (451X10 ^3mm3/group) than B[a]P (1275.6mm^3/group). Before the appearance of premalignant lesions we recorded DB[a,l]P treatments compared to B[a]P produced more DNA damage (8-oxo-dG/B[a]P-N²-dG), less base and nucleotide repair, increased cell proliferation(S phase, and BrdU incorporation), and DNA content (>4N, aneuploid 10.5% increase. Lower levels of mitochondrion induced apoptosis persisted until the formation of oral carcinoma. Early apoptosis in moderate to severe dysplasias developed but remained low in oral cancers characterized by p38MAPK/c-jun expressions while NF-kB increased. p53, a cell cycle and apoptosis regulator, was expressed early and remained high in carcinogen treated mucosa. Bcl-2, an apoptotic inhibitor became elevated with dysplasia while pro-apoptotic markers BaK,and Bax were reduced in expressions. Conclusion: Early markers were identified before the presence of pre-malignant or malignant sites appeared.They are expected to be useful to screen patients at risk for oral cancer.NIH/NCI: CA109940-02