Selective cytotoxic activity of a novel ribonucleoside diphosphate reductase inhibitor MDL-101,731 against thyroid cancer in vitro.
The dramatically increased number of new cases of disseminated children thyroid cancer in Belarus after the Chernobyl accident requires development of novel strategies to treat this disease. In addition to conventional therapy using radioiodine, chemotherapy with new effective drugs can be an alternative kind of treatment. We tested the antitumor activity of (E)-2'-fluoromethylene-2'-deoxycytidine (MDL-101,731), a ribonucleoside diphosphate reductase inhibitor against three thyroid carcinoma cell lines established from anaplastic (8505C), papillary (B-CPAP) and poorly differentiated papillary (BHT-101) cancer. MDL-101,371 decreased both cell growth and DNA synthesis of tumor cells at concentrations lower than 100 nM, while the concentrations higher than 5000 nM showed only moderate effects on growth of normal human fibroblasts. The effects of MDL-101, 371 on tumor cells were associated with induction of apoptosis, as demonstrated by DNA fragmentation assay. Flow cytometric analysis of the expression of apoptosis-related genes revealed the increased levels of Fas-antigen, whereas the levels of Bcl-2 were not significantly influenced in thyroid cancer cells treated with MDL-101,731. These results demonstrated that MDL-101,731 is a potent antitumor agent against cultured thyroid cancer cells due to its ability to induce apoptosis in association with increased Fas expression.
Kotchetkov
R
R
Pediatric Clinic for Hematology and Oncology, University Clinics of Johann Wolfgang Goethe University, Frankfurt am Main, Germany. kotchetk@stud.uni-frankfurt.de
Krivtchik
A A
AA
Cinatl
J
J
Kornhuber
B
B
Cinatl
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000473:pathology*; D002291:Carcinoma, Papillary / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D003841:Deoxycytidine; D014750:Vincristine; D004317:Doxorubicin; D012262:Ribonucleoside Diphosphate Reductase; C086432:tezacitabine; D008727:Methotrexate