• Pearl, Dennis Keith (PI)
  • Lang, James (PI)

Project: Research project

Project Details


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 IV: 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.
Effective start/end date1/1/016/30/05