Synergistic effects of deuterium oxide and gemcitabine in human pancreatic cancer cell lines.
OBJECTIVE
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.
Bader
Yvonne
Y
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Hartmann
Johannes
J
Horvath
Zsuzsanna
Z
Saiko
Philipp
P
Grusch
Michael
M
Madlener
Sibylle
S
Maier
Susanne
S
Oehler
Leopold
L
Fritzer-Szekeres
Monika
M
Heller
Nicole
N
Alken
Rudolf-Giesbert
RG
Krupitza
Georg
G
Szekeres
Thomas
T
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017666:Deuterium Oxide / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014410:Tumor Stem Cell Assay; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003841:Deoxycytidine; D017666:Deuterium Oxide; D000093542:Gemcitabine