Current treatment modalities for cancer combine cytotoxic drugs against DNA and novel targeted drugs affecting signal transduction pathways, which are required for growth progression and metastasizing tumors. Classical chemotherapeutic regimens for gastro-intestinal tumors include antimetabolites based on 5-fluorouracil (5FU), the platinum analog oxaliplatin and the topoisomerase inhibitor irinotecan. The thymidine analog trifluorothymidine (TFT) has been shown to bypass resistance pathways for 5FU derivatives (S-1, UFT, Xeloda) in model systems, while concurrent application with a thymidine phosphorylase inhibitor (TPI) increases the bioavailability of TFT, thereby potentiating the in vivo efficacy of TFT. The formulation TAS-102 is given orally in a 1.0:0.5 molar ratio (TFT:TPI). The formulation is dual-targeted due to the cytotoxic effect of TFT, which is enhanced by TPI, while TPI also exerts antiangiogenic effects by inhibiting thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor. Evidence is accumulating from in vitro and in vivo preclinical studies that these properties favor further combinations with other cytotoxic agents currently being used in the treatment of gastro-intestinal tumors. Also treatment with targeted agents will synergistically down-regulate signal transduction pathways responsible for growth and progression of tumors. In this review, we summarize the available information on ( T AS-102 is a promising novel combination drug, which combines several attractive features. One component is the antiangiogenic effect, which is also intended to enhance its cytotoxic effect. TAS-102 contains the cytotoxic pyrimidine analog 5-trifluoro-2′-deoxythymidine (TFT; trifluridine; 5-trifluromethyl-2′-deoxyuridine; CF 3 dUrd; FTD; F 3 TDR; F 3 Thd) and the potent thymidine phosphorylase (TP) inhibitor (TPI), and is currently evaluated in phase I studies as an oral formulation in a molar ratio of 1.0:0.5 (Fig. 1).The thymidine analog trifluorothymidine was synthesized originally by Heidelberger et al.(1) in 1964, who had already shown that TFT can be phosphorylated by thymidine kinase to its active monophosphate form in uninfected tissues mediating cytotoxicity. TFT has also been evaluated for its antitumor effects and was at least as effective against adenocarcinoma cells as compared to 5-fluoro-2′-deoxyuridine (FdUrd).(3) Based on these pharmacological data, a clinical study on TFT was carried out to evaluate its efficacy in patients with breast and colon carcinomas.(4) Some of the administration schedules have been reported to produce a reduction of tumor size (eight out of 23 breast cancer and one out of six colon cancer). However, these clinical studies were unfortunately discontinued, because of a poor pharmacokinetic profile and side-effects. TFT was also investigated as an antiviral agent and is registered as Viroptic, (5) for use against herpes simplex virus (HSV) infections. The drug was previously approved by the Food and Drug Administration (FDA) in 1980 fo...
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