Synergistic effects of deuterium oxide and gemcitabine in human pancreatic cancer cell lines

Purpose: Pancreatic cancer still remains a treatment-refractory cancer. Standard therapy for metastatic cancer is gemcitabine (dFdC) chemotherapy. Since heavy water (deuterium oxide, D2O) was shown to be active in pancreatic cancer in vitro, we examined the simultaneous or sequential cytotoxic effects of D2O and dFdC in pancreatic cancer cell lines (AsPC-1, BxPC-3, and PANC-1). Moreover, we investigated the effect of D2O treatment on the colony formation of peripheral blood mononuclear cells (PBMNC) as well as the apoptosis inducing activity of D2O and dFdC and the regulation of tumor suppressor gene p21. Results: Simultaneous incubation of human pancreatic carcinoma cells with D2O and dFdC led to a decrease of IC50 values of dFdC alone in all cell lines examined. Sequential application of D2O and dFdC caused synergistic effects. Treatment with 10-30% D2O did not show any significant inhibition effects on the colony formation of peripheral blood mononuclear cells (PBMNC), indicating limited adverse effects of D2O on bone marrow cells. Treatment with D2O in combination with dFdC significantly (p < 0.05) increased the induction of apoptosis in PANC-1 and AsPC-1 cells and led to an overexpression of p21 tumor suppressor gene compared to incubation with dFdC alone. As the combination of D2O and dFdC might offer an additional option for the control of pancreatic cancer, this treatment should be investigated in a pancreas carcinoma animal model in order to scrutinize the in vitro data. (C) 2007 Elsevier Ireland Ltd. All rights reserved.