SYNERGY BETWEEN THE NONCLASSICAL THYMIDYLATE SYNTHASE INHIBITOR AG337(THYMITAQ(R)) AND CISPLATIN IN HUMAN COLON AND OVARIAN-CANCER CELLS

AG337 is a recent non-classical thymidylate synthase inhibitor with pr omising activity and manageable toxicity in phase I clinical trials. I n this study, we investigated the cytotoxic activity of AG337 alone an d in combination with cisplatin in cultured human colon (HT29) and ova rian (2008) cancer cell lines and their derived counterparts selected for their resistance to 5-fluorouracil (5-FU) (HT29-5-FU) and cisplati n (2008C13). We observed that AG337 had potent cytotoxic effects in co lon (IC50 = 0.17 mu M) and ovarian cancer cells (IC50 = 0.65 mu M). Th e cytotoxic activity of AG337 was higher than that of 5-FU in the two models. The activity of AG337 was not significatively affected in 5-FU -resistant HT29-5-FU colon cancer cells characterized by an amplificat ion of the thymidylate synthase gene (IC50 = 0.27 mu M, p = 0.15). Com binations of cisplatin and AG337 exert synergistic activity in both ov arian and colon cancer cells. Interestingly, this synergism was mainta ined in 5-FU- and cisplatin-resistant cells. Therefore, our data encou rage further examination of combinations of AG337 with cisplatin in ca ncer chemotherapy.