Chapter 3 Chapter 3 Carcinogenesis CONTENTS Oral Carcinoma and Smokeless Tobacco Use: A Clinical Profile W. Frederick McGuirt and Anna Wray .................................................. 91 Introduction .................................................................................... 91 Patients ............................................................................................ 91 Field Cancerization ......................................................................... 92 Discussion........................................................................................ 93 References ........................................................................................ 95 Chemical Composition of Smokeless Tobacco Products Klaus D. Brunnemann and Dietrich Hoffmann ..................................... 96 Introduction .................................................................................... 96 Chemical Composition ................................................................... 97 Carcinogenic Agents in ST .............................................................. 97 Carcinogenic N-Nitrosamines ....................................................... 100 TSNA .............................................................................................. 101 Control of Carcinogens in ST ....................................................... 104 References ...................................................................................... 106 Carcinogenesis of Smokeless Tobacco Dietrich Hoffmann, Abraham Rivenson, and Stephen S. Hecht ......... 109 Introduction .................................................................................. 109 Carcinogens in Smokeless Tobacco .............................................. 111 N-Nitrosamines ............................................................................. 113 TSNA .............................................................................................. 113 Discussion...................................................................................... 115 References ...................................................................................... 116 Oncogenes in Head and Neck Cancer Kenneth D. Somers, Suzanne E. Glickman, Suzanne L. Cartwright, Bryan G. Stoll, Stella L. Maurizio, and Gary L. Schechter .................... 119 Introduction .................................................................................. 119 Materials and Methods.................................................................. 120 Results............................................................................................ 120 Discussion...................................................................................... 123 References ...................................................................................... 126 87 Smoking and Tobacco Control Monograph No. 2 Oncogenes in Tobacco-Induced Oral Cancer Madhav G. Deo and Dhananjava Saranath ......................................... 128 Introduction .................................................................................. 128 Oncogene Amplification ............................................................... 129 Expression of Cellular Oncogenes ................................................ 132 RFLP Analysis of L-myc and H-ras Oncogenes .............................. 133 H-ras Point Mutations ................................................................... 134 Identification of a Functional Oncogenes .................................... 136 Conclusions and Future Prospects ................................................ 137 References ...................................................................................... 139 Metabolism and Macromolecular Binding of NNK and NNN, Important Carcinogens in Smokeless Tobacco Stephen S. Hecht, Steven G. Carmella, and Sharon E. Murphy .......... 141 Introduction .................................................................................. 141 Metabolism of NNK and NNN ...................................................... 142 Detection of NNK/NNN-Hemoglobin Adducts............................. 146 Gaps in Assessing the Role of NNK and NNN .............................. 150 Summary ....................................................................................... 151 References ...................................................................................... 151 Role of Nicotine as a Cofactor in Smokeless Tobacco Carcinogenesis Christopher A. Squier and Georgia K. Johnson ................................... 153 Introduction .................................................................................. 153 In Vivo Studies with Nicotine ....................................................... 153 In Vitro Studies with Nicotine ...................................................... 154 Clinical Implications of Studies with Nicotine............................. 155 Future Directions ........................................................................... 159 References ...................................................................................... 159 Perinatal Carcinogenesis by Constituents of Smokeless Tobacco: Animal Models and Potential Human Risk Lucy M. Anderson and Jerry M. Rice.................................................... 161 Introduction .................................................................................. 161 Sensitivity and Susceptibility Factors ............................................ 161 Tobacco-Specific Nitrosamines in Animal Models ....................... 163 Other ST Constituents................................................................... 165 Potential Risk and Future Research ............................................... 166 References ...................................................................................... 169 Interaction Between Smokeless Tobacco-Related Carcinogens and Human Papillomaviruses in the Pathogenesis of Oral Dysplasia and Cancer Joel M. Palefsky, John S. Greeenspan, Tray E. Daniels, Jennifer Berline, Deborah G. Grady, and Virginia Ernster................... 175 Introduction .................................................................................. 175 Methods......................................................................................... 177 Results............................................................................................ 178 Discussion...................................................................................... 178 References ...................................................................................... 181 88 Chapter 3 Identification of Human Papillomavirus DNA in Smokeless Tobacco Keratosis and Premalignant and Malignant Oral Lesions, by PCR Amplification with Consensus Sequence Primus Robert O. Greer, Jr., Kenneth R. Shroyer, and Louise Crosby.............. 183 Introduction .................................................................................. 183 Materials and Methods.................................................................. 184 PCR ................................................................................................ 184 Results............................................................................................ 185 Discussion...................................................................................... 185 References ...................................................................................... 189 Lipids as Factors in the Cell Response to Tobacco Components George S. Schuster, Scott Lubas, Thomas R. Dirksen, and John F. Erbland ..................................................................................... 191 Introduction .................................................................................. 191 Methods......................................................................................... 193 PKC Results .................................................................................... 194 Discussion...................................................................................... 197 References ...................................................................................... 200 Role of Viruses in Oral Carcinogenesis No-Hee Park, Byung-Moo Min, Sheng-Lin Li, Henry M. Cherrick, and Jay Doniger .................................................................................... 202 Introduction .................................................................................. 202 Methods......................................................................................... 203 Results............................................................................................ 206 Discussion...................................................................................... 211 References ...................................................................................... 214 89 Smoking and Tobacco Control Monograph No. 2 90 Chapter 3 Oral Carcinoma and Smokeless Tobacco Use: A Clinical Profile W. Frederick McGuirt and Anna Wray ABSTRACT The clinical profile of 116 patients with oral cavity cancer who used smokeless tobacco exclusive of other known carcinogens, such as smoking tobacco and alcohol, is discussed. The patients, whose average age was 78.4 yr and average use 55.5 yr, had a 1:23 male-to-female ratio and a 14.5:1 white-to-black ratio, both different from national rates for patients with oral cavity cancers. The 116 patients’ course illustrates