Antineoplastic activity of a novel multimeric gemcitabine-monophosphate prodrug against thyroid cancer cells in vitro

Gemcitabine (Gem) is a deoxycytidine analog that is effective against pancr eatic cancer and other malignancies following conversion to the 5'-O-mono-, di- and tli-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 est ablished from anaplastic (8505C), papillary (B-CPAP) and poorly-differentia ted papillary (BHT-101) cancer: GemMP[10] decreased tumor. cell growth at c oncentrations ranging from I to 50 nM. These concentrations were 5- to 10-f old lower than those required for inhibition of tumor cell growth by monome ric Gem. GemMP[10] cytotoxicity occurred via induction of apoptosis. Flow c ytometric analysis of GemMP[10] treated cells increased 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 a ffected These results demonstrated that GemMP[10] is a potent cytotoxic age nt that serves to induce apoptosis in association with increased Fas expres sion in cultured thyroid cancel cell lines.