Triflurdine (Viroptic)

Trifluridine (also called trifluorothymidine or TFT) is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name, Viroptic, by Glaxo Wellcome, now merged into GlaxoSmithKline. The brand is now owned by Monarch Pharmaceuticals, which is wholly owned by King Pharmaceuticals.

Small molecules enhance CRISPR genome editing in pluripotent stem cells.[Pubmed:25658371]

Cell Stem Cell. 2015 Feb 5;16(2):142-7.

The bacterial CRISPR-Cas9 system has emerged as an effective tool for sequence-specific gene knockout through non-homologous end joining (NHEJ), but it remains inefficient for precise editing of genome sequences. Here we develop a reporter-based screening approach for high-throughput identification of chemical compounds that can modulate precise genome editing through homology-directed repair (HDR). Using our screening method, we have identified small molecules that can enhance CRISPR-mediated HDR efficiency, 3-fold for large fragment insertions and 9-fold for point mutations. Interestingly, we have also observed that a small molecule that inhibits HDR can enhance frame shift insertion and deletion (indel) mutations mediated by NHEJ. The identified small molecules function robustly in diverse cell types with minimal toxicity. The use of small molecules provides a simple and effective strategy to enhance precise genome engineering applications and facilitates the study of DNA repair mechanisms in mammalian cells.

Involvement of concentrative nucleoside transporter 1 in intestinal absorption of trifluorothymidine, a novel antitumor nucleoside, in rats.[Pubmed:22076553]

J Pharmacol Exp Ther. 2012 Feb;340(2):457-62.

alphaalphaalpha-Trifluorothymidine (TFT), an anticancer nucleoside analog, is a potent thymidylate synthase inhibitor. TFT exerts its antitumor activity primarily by inducing DNA fragmentation after incorporation of the triphosphate form of TFT into the DNA. Although an oral combination of TFT and a thymidine phosphorylase inhibitor has been clinically developed, there is little information regarding TFT absorption. Therefore, we investigated TFT absorption in the rat small intestine. After oral administration of TFT in rats, more than 75% of the TFT was absorbed. To identify the uptake transport system, uptake studies were conducted by using everted sacs prepared from rat small intestines. TFT uptake was saturable, significantly reduced under Na(+)-free conditions, and strongly inhibited by the addition of an endogenous pyrimidine nucleoside. From these results, we suggested the involvement of concentrative nucleoside transporters (CNTs) in TFT absorption into rat small intestine. In rat small intestines, the mRNAs coding for rat CNT1 (rCNT1) and rCNT2, but not for rCNT3, were predominantly expressed. To investigate the roles of rCNT1 and rCNT2 in TFT uptake, we conducted uptake assays by using Xenopus laevis oocytes injected with rCNT1 complementary RNA (cRNA) and rCNT2 cRNA. TFT uptake by X. laevis oocytes injected with rCNT1 cRNA, and not rCNT2 cRNA, was significantly greater than that by water-injected oocytes. In addition, in situ single-pass perfusion experiments performed using rat jejunum regions showed that thymidine, a substrate for CNT1, strongly inhibited TFT uptake. In conclusion, TFT is absorbed via rCNT1 in the intestinal lumen in rats.

Potentiation of the antitumor activity of alpha, alpha, alpha-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo.[Pubmed:16010427]

Int J Oncol. 2005 Aug;27(2):449-55.

Trifluorothymidine (FTD) is a thymidine analog that exhibits an antitumor activity through its inhibition of thymidylate synthase and its incorporation into DNA. However, FTD is rapidly hydrolyzed to an inactive form by thymidine phosphorylase (TP). We attempted to augment the antitumor activity of FTD by combining it with a potent and reversible inhibitor of TP, 5-chloro-6-(2-imino-propyrrolidin-1-yl) methyl-2, 4 (1H, 3H)-pyrimidinedione hydrochloride (TPI) in human tumor xenografts with a low sensitivity to 5-fluorouracil. The optimum ratio of TPI to FTD was determined by measuring the maximum plasma level of FTD after oral administration and the antitumor effect of FTD on human tumor xenografts in mice. When > 0.5 M of TPI and 1 M of FTD (10 mg/kg) were co-administered, the plasma FTD levels in mice and monkeys were elevated, almost reaching a maximal and constant value of 20-30 microg/ml and 15 microg/ml, respectively. When human gastrointestinal cancer cell lines (DLD-1, CO-3 and AZ521) were xenografted into nude mice, the antitumor activity of FTD was augmented by the co-administration of TPI, compared to that of FTD alone, and the ED50 value, used to indicate the antitumor effect, reached a maximum value (about 25, 20, and 10 mg/kg in the DLD-1, CO-3, and AZ521 tumors, respectively) when > 0.5 M of TPI was combined with 1 M of FTD. The oral administration of TPI markedly improved the FTD-induced toxicity, as evaluated by the decrease in the body weight of the mice. These results suggested that the optimum ratio of FTD to TPI was 1:0.5 M, enabling a high antitumor activity and a low toxicity. We further evaluated whether TPI inhibits TP-induced angiogenesis in a gelatin-sponge mouse model, based on the finding that TP is identical to platelet-derived endothelial cell growth factor. Ten and 30 mg/kg administration of TPI significantly inhibited TP-induced neovascularization in a dose-dependent manner in a mouse model. The above results suggest that the combination of TPI and an antitumor nucleoside, FTD, not only enhances the antitumor efficacy and decreases the toxicity of FTD, but also suppresses TP-induced angiogenesis.

Trifluridine (Trifluorothymidine; 5-Trifluorothymidine; TFT) is an irreversible thymidylate synthase inhibitor, and thereby suppresses DNA synthesis. Trifluridine is an antiviral drug for herpes simplex virus (HSV) infection.

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