title: Synergy between the non-classical thymidylate synthase inhibitor AG337 (Thymitaq) and cisplatin in human colon and ovarian cancer cells.
abstract: AG337 is the recent non-classical thymidylate synthase inhibitor with promising activity and manageable toxicity in phase I clinical trials. In this study, we investigated the cytotoxic activity of AG337 alone and in combination with cisplatin in cultured human colon (HT29) and ovarian (2008) cancer cell lines and their derived counterparts selected for their resistance to 5-fluorouracil (5-FU) (HT29-5-FU) and cisplatin (2008C13). We observed that AG337 had potent cytotoxic effects in colon (IC50 = 0.17 MicroM) and ovarian cancer cells (IC50 = 0.65 microM). The cytotoxic activity of AG337 was higher than that of 5-FU in the two models. The Activity of AG337 was not significantly affected in 5-FU-resistant HT29-5-FU colon cancer cells characterized by an amplification of the thymidylate synthase gene (IC50 = 0.27 microM, p = 0.15). Combinations of cisplatin and AG337 exert synergistic activity in both ovarian and colon cancer cells. Interestingly, this synergism was maintained in 5-FU- and cisplatin-resistant cells. Therefore, our data encourage further examination of combinations of AG337 with cisplatin in cancer chemotherapy.
authors.affiliation: Unité INSERM U55, Institut Fédératif de Recherches du Centre Hospitalo-Universitaire Paris Saint-Antoine, Hôpital Saint-Antoine, France.
authors.forename: E
authors.initials: E
authors.lastname: Raymond
authors.forename: S
authors.initials: S
authors.lastname: Djelloul
authors.forename: C
authors.initials: C
authors.lastname: Buquet-Fagot
authors.forename: J
authors.initials: J
authors.lastname: Mester
authors.forename: C
authors.initials: C
authors.lastname: Gespach
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; C099178:nolatrexed; D002945:Cisplatin; D005472:Fluorouracil