title: Antineoplastic activity of a novel multimeric gemcitabine-monophosphate prodrug against thyroid cancer cells in vitro.
abstract: Gemcitabine (Gem) is a deoxycytidine analog that is effective against pancreatic cancer and other malignancies following conversion to the 5'-O-mono-, di- and tri-phosphate forms. We evaluated the cytotoxicity of GemMP[10], a novel multimeric form of 2'-deoxy-2',2"-difluorocytidine-5'-O-monophosphate (gemcitabine monophosphate) against three thyroid carcinoma cell lines established from anaplastic (8505C), papillary (B-CPAP) and poorly-differentiated papillary (BHT-101) cancer. GemMP[10] decreased tumor cell growth at concentrations ranging from 1 to 50 nM. These concentrations were 5- to 10-fold lower than those required for inhibition of tumor cell growth by monomeric Gem. GemMP[10] cytotoxicity occurred via induction of apoptosis. Flow cytometric analysis of GemMP[10] treated cells revealed growth arrest in S-phase. Fas-antigen expression was increased in thyroid cancer cells treated with GemMP[10], whereas Fas-L and Bcl-2 expression were not significantly affected. These results demonstrated that GemMP[10] is a potent cytotoxic agent that serves to induce apoptosis in association with increased Fas expression in cultured thyroid cancer cell lines.
authors.affiliation: Pediatric Clinic for Hematology and Oncology, University Clinics of Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kotchetkov
authors.forename: B
authors.initials: B
authors.lastname: Gröschel
authors.forename: W H
authors.initials: WH
authors.lastname: Gmeiner
authors.forename: A A
authors.initials: AA
authors.lastname: Krivtchik
authors.forename: E
authors.initials: E
authors.lastname: Trump
authors.forename: M
authors.initials: M
authors.lastname: Bitoova
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
authors.forename: B
authors.initials: B
authors.lastname: Kornhuber
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011355:Prodrugs; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D003841:Deoxycytidine; D000093542:Gemcitabine