Oral squamous cell carcinoma (SCC) has a multifactorial etiology with putative initiating and/or promoting agents comprised of both extrinsic (tobacco/alcohol) and intrinsic (host immune status, Fe deficiency, anemia) risk factors. Paradoxically, two host defense mechanisms (the P450 family of microsomal enzymes and host phagocytic cells), which function to detoxify xenobiotics and microbes respectively, can also result in cancer promoting effects, e.g., P450 conversion of the tobacco associated carcinogens (TAC) to activated forms which bind to DNA and the mutagenic effects of reactive oxygen intermediates (ROI) released beyond the phago- lysosome. Both of these host defense systems employ oxidative pathways, resulting in increased to the constitutive levels of oxidant challenge that are present due to normal cellular oxidative carcinogens as well as the formation and degradation of RO1 are critical determinants which dictate whether the overall outcome of P450 or phagocytic activation will be cytoprotective or injurious. We maintain that sustained P450 activity (augmented by risk factors such as alcohol and tobacco) in conjunction with cellular oxidant stress is integral in instigating cellular perturbations which result in the initiation phase of oral SCC. Four general questions are addressed in this study: 1) What enzymes are responsible for the metabolism of tobacco associated carcinogens in the oral activity? 2) How does ethanol modulate oral mucosal carcinogen metabolism? 3) How do oral mucosa cells cope with oxidant challenge? 4) What are the in vitro cellular and in vivo tissue responses to oxidant challenge? These questions will be addressed by the following Specific Aims.
Aim I : Determine the capacity or oral mucosal tissue to metabolize tobacco-associated carcinogens (TAC).
Aim II : Determine the effects of ethanol and specific complex mixtures of carcinogens on normal, dysplastic, and SCC oral mucosa.
Aim III : Evaluate cellular capacity to inactivate and bioenergetically respond to reactive oxygen intermediates (ROI).
Aim I V: Evaluate in vivo cellular capacity to express cytoprotective enzymes in response to pro-inflammatory local mediators in inflamed normal oral mucosa, dysplastic oral mucosa, and oral SCC explants. Our Research Project is designed to provide insight into the cellular events that occur during the initiation phase of oral cancer. Hopefully, our data will result not only in an understanding of pre- neoplastic/neoplastic cellular biochemistry, but will provide a basis for specific chemoprevention.
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