tiazofurin and Pancreatic-Neoplasms

Since taxol (NSC 125975) and tiazofurin (NSC 286193) attack at two different sites in microtubular synthetic processes, we tested the rationale that the two drugs might be synergistic in human ovarian (OVCAR-5), pancreatic (PANC-1) and lung carcinoma (H-125) cells and in rat hepatoma 3924A cells. In human OVCAR-5, PANC-1, H-125 and rat 3924A cells, for taxol the anti-proliferative IC50 was 0.05, 0.06, 0.03 and 0.04 microM, respectively; for tiazofurin IC50 = 8.3, 2.3, 1.8 and 6.9 microM. Thus, the concentrations for taxol required for IC50 for inhibiting cell proliferation were 166-, 38-, 60- and 173-fold lower than those for tiazofurin. Taxol and tiazofurin proved synergistic in all four cell lines tested. The synergism of taxol with tiazofurin should have implications in the clinical treatment of human solid tumors with particular relevance to ovarian, pancreatic, lung and hepatocellular carcinomas.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinoma; Carcinoma, Adenosquamous; Cell Division; Drug Screening Assays, Antitumor; Drug Synergism; Female; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Liver Neoplasms, Experimental; Lung Neoplasms; Ovarian Neoplasms; Paclitaxel; Pancreatic Neoplasms; Rats; Ribavirin; Spindle Apparatus; Tumor Cells, Cultured

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.

Topics: Animals; Antimetabolites, Antineoplastic; Cell Differentiation; Cell Line; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Female; Gemcitabine; Humans; IMP Dehydrogenase; Kinetics; Leukemia, Promyelocytic, Acute; Liver Neoplasms, Experimental; Models, Biological; Ovarian Neoplasms; Pancreatic Neoplasms; Rats; Ribavirin; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Stem Cell Assay

Tiazofurin and 8-Cl-cAMP are novel chemotherapeutic agents shown to be effective against various cancer cells in vitro and in vivo. They act through distinct mechanisms that might modulate the signal transduction pathway, which causes growth inhibition, differentiation and down-regulation of c-ras and c-myc oncogene expression. We examined the effects of tiazofurin and 8-Cl-cAMP on colony formation of HT-29 human colon cancer and BxPC-3 and PANC-1 human pancreatic cancer cell lines. The IC50 of 8-Cl-cAMP was 0.1 and 0.2 microM in the pancreatic and colon cancer cell lines, respectively, and tiazofurin yielded IC50s from 4 (PANC-1) to 18 microM (HT-29). Simultaneous incubation with 8-Cl-cAMP and tiazofurin had additive effects on the inhibition of colony formation in the three examined cell lines. These results indicate possible clinical usefulness of a combination of tiazofurin and 8-Cl-cAMP in the treatment of colon and pancreatic carcinomas.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Synergism; Humans; IMP Dehydrogenase; Pancreatic Neoplasms; Ribavirin; Signal Transduction; Tumor Cells, Cultured; Tumor Stem Cell Assay