Abstract
Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102 (also named TFTD), which consists of FTD and a thymidine phosphorylase inhibitor. FTD is supposed to exert its cytotoxicity via massive misincorporation into DNA, but the underlying mechanism of FTD incorporation into DNA and its correlation with cytotoxicity are not fully understood. The present study shows that several antibodies against 5-bromo-2′-deoxyuridine (BrdU) specifically cross-react with FTD, either anchored to bovine serum albumin or incorporated into DNA. These antibodies are useful for several biological applications, such as fluorescence-activated cell sorting, fluorescent immunostaining and immunogold detection for electron microscopy. These techniques confirmed that FTD is mainly incorporated in the nucleus during S phase in a concentration-dependent manner. In addition, FTD was also detected by immunohistochemical staining in paraffin-embedded HCT-116 xenograft tumors after intraperitoneal administration of FTD. Intriguingly, FTD was hardly detected in surrounding matrices, which consisted of fibroblasts with marginal expression of the nucleoside transporter genes SLC29A1 and SLC29A2. Thus, applications using anti-BrdU antibodies will provide powerful tools to unveil the underlying mechanism of FTD action and to predict or evaluate the efficacy and adverse effects of TAS-102 clinically.
Highlights
TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride, a thymidine phosphorylase inhibitor (TPI) that inhibits degradation of FTD, at a molar ratio of 1:0.51
The C-5 position of the pyrimidine ring is often replaced by a halogen atom, i.e., bromine, iodine, or chlorine, in nucleoside analogs that are utilized as markers of active DNA synthesis[16,17]
It is reasonable to assume that some of the commercially available anti-bromo-2′ -deoxyuridine (BrdU) antibodies may bind to FTD with enough affinity and selectivity to allow the detection of FTD incorporated into the genomic DNA of cancer cells
Summary
TAS-102 ( named TFTD) is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride, a thymidine phosphorylase inhibitor (TPI) that inhibits degradation of FTD, at a molar ratio of 1:0.51. We found that several anti-BrdU antibodies cross-react with FTD, either anchored to bovine serum albumin (BSA) or incorporated into DNA. Using these antibodies, we confirmed that FTD incorporation into DNA was mainly detected in the nuclei of FTD-treated human cancer cell lines during S phase. One antibody (3D4) detected FTD incorporated into DNA even in paraffin-embedded xenograft tissues from FTD-treated mice. Using these antibodies, clinical applications may be possible to predict the efficacy or adverse effects of the novel antitumor drug TAS-102
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