The long- term objective of this application is to investigate the role of dopamine (DA) in the pathogenesis and treatment of gastric cancer. Very recently, we demonstrated that there is a complete absence of endogenous DA in human gastric cancer tissues and that treatment with exogenous DA retards the growth of a non- metastatic human gastric cancer xenograft. There are also reports indicating that low doses of DA inhibit the production of reactive oxygen species (ROS). Furthermore, because ROS play an important role in the induction of gastric cancer, we hypothesized that DA could control gastric tumorigenesis by regulating ROS production in gastric tissues. The experiments proposed here are designed to investigate the status of endogenous stomach DA, its relationship with ROS produced during gastric tumorigenesis, and the molecular pathways by which DA regulates ROS production in gastric tissues. Finally, we will also examine the possibility that DA might be utilized alone or in combination with conventional chemotherapeutic drugs in a highly metastatic gastric cancer preclinical model.
Aim I. To determine the role of endogenous stomach dopamine in gastric tumorigenesis. Experimental Design: The status of ROS, endogenous stomach DA and tyrosine hydroxylase , the rate limiting enzyme for DA synthesis will be examined in gastric tissues collected from wild type and DA receptor knock-out Helicobacter felis (H.felis) - inoculated mice.
Aim II. To elucidate the molecular mechanism of dopamine mediated inhibition of gastric cancer. Experimental Design: The signaling pathways through which DA inhibits ROS in gastric epithelial cells will be elucidated.
Aim III. To investigate the effect of DA in metastatic gastric cancer. Experimental Design: The effect of will be tested either alone or in combination with conventional anticancer drugs in a highly metastatic orthotopic human gastric cancer xenograft. The knowledge generated from this study will be important to gain insight into the pathogenesis of gastric cancer, identify high risk individuals, and develop newer therapies to combat advanced gastric cancer (majority of gastric cancer patients in the United States are seen in an advanced clinical stage), which, as of yet, has no significant treatment. ? ?
