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

Cancer of the oral cavity is a serious disease, affecting about 30,000 individuals in US annually. There are several animal models of oral cancer, but each has certain disadvantages. As a new model, we investigated whether topical application of the 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, respectively. B6C3F1 lacI mice received DB[a,l]P (0, 3, 6, 12 nmol) 3× per week. B6C3F1 mice received the same doses and also 24 nmol. At 38 weeks mutagenesis was measured in oral tissues in lacI mice. For the high dose group, the mutant fraction (MF) in upper mucosa and tongue increased about twofold relative to that in vehicle‐alone. The increases were statistically significant. The mutational profile in the DB[a,l]P‐induced mutants was compared with that induced by benzo[a]pyrene (BaP) in oral tissue. BaP is mutagenic in many tissues when administered by gavage. The mutational profile for DB[a,l]P was more similar to that reported for p53 mutations in head and neck cancers than was that of BaP. At 47 weeks, oral squamous cell carcinomas (OSCC) were found in 31% of the high‐dose B6C3F1 group. Elevations of p53 and COX‐2 protein were observed in tumor and dysplastic tissue. As 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, the treatment protocol described here may represent a new and relevant model for cancer of the oral cavity.

[1]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[2]  M. George,et al.  Mutations induced by benzo[a]pyrene and dibenzo[a,l]pyrene in lacI transgenic B6C3F1 mouse lung result from stable DNA adducts. , 2008, Mutagenesis.

[3]  S. Amin,et al.  Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide. , 2007, Mutation research.

[4]  R. Norman,et al.  Comparative mutational profiles of the environmental mammary carcinogen, 6-nitrochrysene and its metabolites in a lacI mammary epithelial cell line. , 2007, Carcinogenesis.

[5]  Clifton D Fuller,et al.  Conditional survival in head and neck squamous cell carcinoma , 2007, Cancer.

[6]  Takuji Tanaka,et al.  Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. , 2005, International journal of oncology.

[7]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[8]  S. Amin,et al.  A Highly Abbreviated Synthesis of Dibenzo[def,p]chrysene and Its 12-Methoxy Derivative, a Key Precursor for the Synthesis of the Proximate and Ultimate Carcinogens of Dibenzo[def,p]chrysene. , 2004, Journal of Organic Chemistry.

[9]  D. Desai,et al.  Effects of 3H-1,2-dithiole-3-thione, 1,4-phenylenebis(methylene)selenocyanate, and selenium-enriched yeast individually and in combination on benzo[a]pyrene-induced mutagenesis in oral tissue and esophagus in lacZ mice. , 2004, Mutation research.

[10]  S. Tickoo,et al.  Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice , 2004, Clinical Cancer Research.

[11]  Stephen S. Hecht,et al.  Tobacco carcinogens, their biomarkers and tobacco-induced cancer , 2003, Nature Reviews Cancer.

[12]  A. Luch,et al.  Cytochrome P450 1B1 determines susceptibility to dibenzo[a,l]pyrene-induced tumor formation. , 2002, Chemical research in toxicology.

[13]  Yoshinobu Hirose,et al.  Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. , 2002, Carcinogenesis.

[14]  T. Buterin,et al.  Unrepaired fjord region polycyclic aromatic hydrocarbon-DNA adducts in ras codon 61 mutational hot spots. , 2000, Cancer research.

[15]  G. Shklar,et al.  Development of Experimental Oral Carcinogenesis and its Impact on Current Oral Cancer Resecuch , 1999, Journal of dental research.

[16]  T. Mikami,et al.  Comparison between in vivo mutagenicity and carcinogenicity in multiple organs by benzo[a]pyrene in the lacZ transgenic mouse (Muta Mouse). , 1998, Mutation research.

[17]  S. Nesnow,et al.  Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung. , 1997, Carcinogenesis.

[18]  M. Tang,et al.  Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53 , 1996, Science.

[19]  J. Pelling,et al.  Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Tornaletti,et al.  The ultimate carcinogen of 4-nitroquinoline 1-oxide does not react with Z-DNA and hyperreacts with B-Z junctions. , 1994, Nucleic acids research.

[21]  N. V. Ramakrishna,et al.  Tumor-initiating activity and carcinogenicity of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene at low doses in mouse skin. , 1993, Carcinogenesis.

[22]  N. V. Ramakrishna,et al.  Comparative dose-response tumorigenicity studies of dibenzo[a,l]pyrene versus 7, 12-dimethylbenz[a]anthracene, benzo[a and two dibenzo[a,l]pyrene dihydrodiols in mouse skin and rat mammary gland , 1991 .

[23]  E. Cavalieri,et al.  Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a]pyrenes: the very potent environmental carcinogen dibenzo[a, l]pyrene , 1989, Journal of Cancer Research and Clinical Oncology.

[24]  S. Hecht,et al.  Induction of oral cavity tumors in F344 rats by tobacco-specific nitrosamines and snuff. , 1986, Cancer research.

[25]  M. Snook,et al.  The ldentification of High Molecular Weight Polynuclear Aromatic Hydrocarbons in a Biologically Active Fraction of Cigarette Smoke Condensate , 1977 .

[26]  L. L. Ansell,et al.  THE SYNTHESIS OF 1,2,3,7,8,9-HEXAHYDRODIBENZO(DEF,MNO)CHRYSENE AND THE USE OF HYDRIODIC ACID-RED PHOSPHORUS IN THE DEOXYGENATION OF KETONES , 1976 .

[27]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[28]  Magali Olivier,et al.  TP53 mutations in human cancers: origins, consequences, and clinical use. , 2010, Cold Spring Harbor perspectives in biology.

[29]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[30]  D W Gaylor,et al.  A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay. , 1998, Carcinogenesis.

[31]  J. Heddle,et al.  System issues: A test for neutrality of mutations of the lacZ transgene , 1996, Environmental and molecular mutagenesis.

[32]  Takuji Tanaka,et al.  Chemoprevention of oral carcinogenesis. , 1995, European journal of cancer. Part B, Oral oncology.

[33]  J. Leininger,et al.  Tumours of the oral cavity, pharynx, oesophagus and stomach. , 1994, IARC scientific publications.

[34]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[35]  L. L. Ansell,et al.  THE SYNTHESIS OF 1,2,3,7,8,9-HEXAHYDRODIBENZO[def, mno]CHRYSENE AND THE USE OF HYDRIODIC ACID-RED PHOSPHORUS IN THE DEOXYGENATION OF KETONES , 1976 .