Abstract 1783: Trifluorothymidine incorporation into DNA strongly enforces the potential of TAS-102 and leads to remarkably prolonged survival of cancer patients

Abstract

Abstract TAS-102 is a novel oral antitumor agent, consisting of trifluorothymidine (FTD) as the active component and thymidine phosphorylase inhibitor (TPI) which prevents degradation of FTD. In a double-blind randomized phase II study conducted in Japan, TAS-102 significantly improved overall survival of metastatic colorectal cancer patients, compared with placebo (TAS-102, n = 112; Placebo, n = 57; median OS, 9.0 vs. 6.6 months; HR, 0.56; p = 0.001). We investigated mechanisms of action of TAS-102 to understand how prognosis of cancer patients was improved. In vitro study, FTD was previously reported to have two mechanisms, FTD incorporation into DNA and thymidylate synthase (TS) inhibition. In this study, we show that FTD incorporation into DNA is the main mechanism of TAS-102 and the key to potentiate anti-tumor efficacy of FTD. We found that although TS inhibition of FTD reduced rapidly after drug removal, the cytotoxicity of FTD did not diminish. On the other hand, the cytotoxicity of FdUrd diminished after drug removal. As compared to FdUrd, FTD was incorporated into DNA to a greater extent by the time drug was removed. It is thought that the FTD retained in DNA contributes to sustained growth inhibition. Therefore, FTD incorporation into DNA is considered to be essential for enforcing the potential of FTD. Additionally, we investigated the in vivo potency of TAS-102 by using daily divided oral administration since this regimen was the most optimal to maximize FTD incorporation into DNA. Interestingly, TAS-102 showed marked tumor growth delay even after end of the administration and remarkable prolonged survival of mice implanted with KM20C derived from human colon cancer. Collectively, these data suggest that TAS-102 improved survival of cancer patients primarily due to FTD incorporation into DNA. FTD is previously reported to affect DNA structure, and we speculate that TAS-102 exerts its anti-tumor effects through interfering with DNA function once adequate amounts of FTD have been accumulated in the DNA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1783. doi:1538-7445.AM2012-1783