Synergistic action of tiazofurin and difluorodeoxycytidine on differentiation and cytotoxicity.
Tiazofurin (TR), an inhibitor of IMP dehydrogenase, causes remissions and induced differentiation in human leukemia through lowering the concentrations of GTP and dGTP. A deoxycytidine analog, difluorodeoxycytidine (DFDC), is an anti-tumor agent phosphorylated by deoxycytidine kinase, resulting in decreased concentration of dCTP, leading to inhibition of DNA synthesis. In HL-60 cells DFDC induced differentiation and inhibited proliferation in a dose-dependent manner (IC50 = 4 nM); TR provided synergism with DFDC. DFDC inhibited proliferation in OVCAR-5 human ovarian carcinoma cells (IC50 = 25 nM) and colony formation in PANC-1 human pancreatic carcinoma cells (IC50 = 2 nM) and rat hepatoma 3924A cells (IC50 = 22 nM). TR and DFDC are synergistically cytotoxic in hepatoma cells and additive in PANC-1 cells. The two drugs together should be helpful in treating leukemias and solid tumors in humans.
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000187:drug effects; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D008114:Liver Neoplasms, Experimental; D008954:Models, Biological; D010051:Ovarian Neoplasms; D010190:Pancreatic Neoplasms; D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D012254:Ribavirin; D014212:Tretinoin; D007168:IMP Dehydrogenase; D013755:Tetradecanoylphorbol Acetate; C033706:tiazofurin; D000093542:Gemcitabine