Pharmacologic Ascorbate as a Radiosensitizer
There is a tremendous clinical need to improve local therapies for pancreatic cancer, with one-third of patients dying due to the consequences of local disease. Local therapy includes ionizing radiation either alone or in combination with chemotherapy. Thus, there are significant numbers of patients who would benefit from improvements in the efficacy of radio- and chemotherapy of pancreatic cancer. Aberrant redox conditions are observed more frequently in pancreatic cancer cells than in their normal counterparts. Exposure of dividing cells to low concentrations of oxidants actually stimulates cell growth and division, while higher concentrations result in growth arrest and necrosis. Pharmacologic ascorbate (P-AscH−) given intravenously produces high concentrations of hydrogen peroxide (H2O2) that are cytotoxic to tumor cells, whereas normal cells are resistant to this oxidative insult. In addition, P-AscH− selectively sensitizes pancreatic cancer cells to ionizing radiation but protects normal pancreatic ductal epithelia, intestinal epithelia, and vascular endothelium against radiation-induced injury. P-AscH− combined with chemoradiation is safe and well-tolerated and may lead to overall clinical benefit in patients with pancreatic cancer. The fundamental difference in redox conditions of tumor versus normal cells enables P-AscH− radiosensitization in tumor cells and radioprotection of normal cells.