Antitumor Activity and Pharmacokinetics of TAS‐106, l‐(3‐C‐Ethynyl‐β‐D‐ribo‐pentofuranosyl)cytosine

We examined the effects of dosage schedule on antitumor activity in vitro and in vivo to determine the optimal administration schedule for a new nucleoside antimetabolite l‐(3‐C‐ethynyl‐β‐D‐ribo‐pentofuranosyl)cytosine (ECyd, TAS‐106). The cytotoxicity of TAS‐106 in vitro against human tumors was evaluated at three drug exposure periods. TAS‐106 exhibited fairly potent cytotoxicity even with 4 h exposure, and nearly equivalent and sufficiently potent cytotoxicity with 24 and 72 h exposures. These results suggest that long‐term exposure to TAS‐106 will not be required to achieve maximal cytotoxicity. The antitumor activity of TAS‐106 in vivo was compared in nude rat models bearing human tumors on three administration schedules, once weekly, 3 tunes weekly, and 5 tunes weekly for 2 or 4 consecutive weeks. TAS‐106 showed strong antitumor activity without serious toxicity on all three schedules, but the antitumor activity showed no obvious schedule‐dependency in these models. When tumor‐bearing nude rats were given a single i.v. dose of [(3)H]TAS‐106, tumor tissue radioactivity tended to remain high for longer periods of time as compared to the radioactivity in various normal tissues. Furthermore, when the metabolism of TAS‐106 in the tumor was examined, it was found that TAS‐106 nucleotides (including the active metabolite, the triphosphate of TAS‐106) were retained at high concentrations for prolonged periods. These pharmacodynamic features of TAS‐106 may explain the strong antitumor activity without serious toxicity, observed on intermittent administration schedules, in nude rat models with human tumors. We therefore consider TAS‐106 to be a promising compound which merits further investigation in patients with solid tumors.