UCSF

Cancer pain creates a poor quality of life for cancer patients. Chronic

cancer pain is a major public health problem in which little progress has been made in treatment. In this dissertation we propose that pain is the result of imbalance between algesic and analgesic mediators within the cancer microenvironment. Furthermore, this imbalance arises from downregulation by hypermethylation of genes coding for analgesic mediators, and re-expression of these mediators by demethylating drugs produces analgesia. We determine whether EDNRB and OPRM1, genes of receptors mediating analgesia, are hypermethylated in the tumors of oral cancer patients, compared to normal and oral dysplasia controls. To determine whether the expression of these genes mediates analgesia, we create an orthotopic oral cancer mouse model, where we re-express the EDNRB or OPRM1 gene using adenoviruses. Re-expression of EDNRB results in mechanical analgesia, and re-expression of OPRM1 results in mechanical and thermal analgesia in the mouse cancer pain model. Finally, we determine the analgesic potential of demethylating drugs decitabine and zebularine in the mouse cancer model. We show that combination therapy with these two drugs results in an antiproliferative and analgesic effect in the mouse model.