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...
Trifluorothymidine (TFT) is part of the oral drug formulation TAS-102. Both 5-fluorouracil (5-FU) and TFT can inhibit thymidylate synthase and be incorporated into DNA. TFT shows only moderate cross-resistance to 5-FU. Therefore, we examined whether mechanistic differences in cell death could underlie their different modes of action in colorectal cancer cell lines (WiDR, Lovo92 and Colo320). Drug cytotoxicity was determined by SRB-and clonogenic assays, cell death by flow cytometry (PI and annexin V), caspase cleavage by Western blotting and activity assays and in vivo activity in the hollow fiber assay. The IC 50 values of TFT were 1-6 fold lower than for 5-FU, and clonogenic survival was less than 0.9% at 3 lM TFT, while 2-20% of the cells still survived after 20 lM 5-FU. In general, TFT was a more potent inducer of apoptosis than 5-FU, although the contribution of caspases varied between the used cell lines and necrosis-like cell death was detected. Accordingly, both drugs induced caspase (Z-VAD) independent cell death and lysosomal cathepsin B was involved. Activation of autophagy recovery mechanisms was only triggered by 5-FU, but not by TFT as determined by LC3B expression and cleavage. Inhibition of autophagy by 3-MA in 5-FU exposed cells reduced cell survival. Also, in vivo TFT (as TAS-102) caused more cell death than a 5-FU formulation. We conclude that TFT and 5-FU induce cell death via both caspase-dependent and independent mechanisms. The TFT was more potent than 5-FU, because it induces higher levels of cell death and does not elicit an autophagic survival response in the cancer cell lines. This provides a strong molecular basis for further application of TFT in cancer therapy.5-Fluorouracil (5-FU) based therapy is part of the standard therapy for colorectal (CRC) and breast cancer. In order to exert its cytotoxic effect, 5-FU has to be activated to its monophosphate form, FdUMP. FdUMP is a strong irreversible inhibitor of thymidylate synthase (TS) by forming a stable ternary complex. In its triphosphate forms, FUTP and FdUTP, 5-FU can be incorporated into the RNA and DNA, respectively. 1 The effect of 5-FU in combination with leucovorin has increased survival, 2 but resistance is often encountered. 5-FU-resistance is related to a decreased level of 5-FUactivating enzymes, including orotate phosphoribosyl-transferase and uridine kinase, 3 and an increased expression of the target TS. 4 Recent improvements have been made by replacing bolus injections and inconvenient continuous infusions by oral fluoropyrimidine formulations, such as Xeloda (capecitabine) and UFT. 5 Another type of oral formulation, TAS-102, has recently been introduced into the clinic and consists of trifluorothymidine (TFT), in combination with a specific inhibitor of thymidine phosphorylase (TP), TPI. TAS-102, is currently tested in phase II studies against colorectal and gastric cancer. 6 Similar to 5-FU, TFT can inhibit TS in its monophosphate form (TF-TMP), 7 however TFT does not form a ternary complex as for 5-FU, but binds co...
Oxaliplatin (OHP) is an anticancer agent that acts by formation of Platinum-DNA (Pt-DNA) adducts resulting in DNA-strand breaks and is used for the treatment of colorectal cancer. The pyrimidine analog trifluorothymidine (TFT) forms together with a thymidine phosphorylase inhibitor (TPI) the anticancer drug formulation TAS-102, in which TPI enhances the bioavailability of TFT in vivo. In this in vitro study the combined cytotoxic effects of OHP with TFT were investigated in human colorectal cancer cells as a model for TAS-102 combinations. In a panel of five colon cancer cell lines (WiDr, H630, Colo320, SNU-C4 and SW1116) we evaluated the OHP-TFT drug combinations using the multiple drug -effect analysis with CalcuSyn software, in which the combination index (CI) indicates synergism (CIo0.9), additivity (CI ¼ 0.9 -1.1) or antagonism (CI41.1). Drug target analysis was used for WiDr, H630 and SW1116 to investigate whether there was an increase in Pt-DNA adduct formation, DNA damage induction, cell cycle delay and apoptosis. Trifluorothymidine combined with OHP resulted in synergism for all cell lines (all CIo0.9). This was irrespective of schedule in which either one of the drugs was kept at a constant concentration (using variable drug ratio) or when the two drugs were added in a 1 : 1 IC 50 -based molar ratio. Synergism could be increased for WiDr using sequential drug treatment schedules. Trifluorothymidine increased Pt-DNA adduct formation significantly in H630 and SW1116 (14.4 and 99.1%, respectively; Po0.05). Platinum-DNA adducts were retained best in SW1116 in the presence of TFT. More DNA-strand breaks were induced in SW1116 and the combination increased DNA damage induction (420%) compared with OHP alone. Exposure to the drugs induced a clear cell-cycle S-phase arrest, but was dose schedule and cell line dependent. Trifluorothymidine (TFT) and OHP both induced apoptosis, which increased significantly for WiDr and SW1116 after TFT -OHP exposure (18.8 and 20.6% respectively; Po0.05). The basal protein levels of ERCC1 DNA repair enzyme were not related to the DNA damage that was induced in the cell lines. In conclusion, the combination of TFT with the DNA synthesis inhibitor OHP induces synergism in colorectal cancer cells, but is dependent on the dose and treatment schedule used.
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