OXIDATIVE DAMAGE IN PANCREATITIS AND PANCREATIC NEOPLASIA

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

Carcinoma of the pancreas if the fifth leading cause of cancer death in the United States; treatment for established carcinoma is largely ineffective, with mean survival measured in months. The possibility of detection of early neoplasms in a high-risk group forms the rationale for the current proposal. Chronic pancreatitis is the most significant risk factor for pancreatic cancer yet identified. Acute and chronic pancreatitis are associated with injury from reactive oxygen radicals. Oxidative damage to DNA during the development of chronic pancreatitis may lead to mutations which ultimately cause the development of subsequent pancreatic cancer. The eventual fate of oxidatively damaged cells may depend on anti-oxidant defense against further injury, changes in the ability of cells to undergo apoptosis, or changes in cell proliferation. These further changes may be a result of continued oxidative damage. In the first specific aim of the current proposal, normal pancreas and tissue with chronic pancreatitis and pancreatic cancer will be examined for markers of oxidative DNA damage, antioxidant defense, apoptosis, and proliferation. The second specific aim will address whether oxidative damage sensitizes the pancreatic duct epithelium to further changes in antioxidant defense, apoptosis and proliferation. We will determine whether antioxidant treatment can prevent these changes. This aim will also determine if cells exposed to oxidative stress are more sensitive to carcinogen challenge than normal duct cells. To examine similar questions in an in vivo model, chronic pancreatitis will be induced in hamsters and the resultant oxidative damage in pancreatic tissue measured, as well as changes in antioxidant defense, apoptosis, and proliferation. These animals will be observed for the development of spontaneous tumors and tested for the development of cancer in response to low doses of the carcinogen N-nitrosobis (2-oxopropyl) amine (BOP). Animals with chronic pancreatitis will be treated with antioxidants during the course of pancreatitis will be analyzed for markers of oxidative damage, antioxidant defense, apoptosis or proliferation which are found to be associated with neoplastic change in Aims 1 and 2. Aim 2, we will establish the feasibility of measuring these markers in pancreatic juice and brushing, determine the incidence of marker positivity in patients with chronic pancreatitis, validate the markers, and develop a cohort of chronic pancreatitis patients for long=term cancer surveillance.