PURPOSE: Trifluridine (TFT) is an antitumor component of a novel nucleoside 
antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride 
(thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable 
mechanism of antitumor activity and hematological toxicity. The objective of 
this study was to examine the TFT incorporation into tumor- and white blood 
cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT 
effect on the colony formation of mouse bone marrow cells was also investigated.
METHODS: Pharmacokinetics of TFT was determined in nude mice after single oral 
administration of TAS-102, while the antitumor activity and body weight change 
were evaluated in the tumor-bearing nude mice after multiple oral 
administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were 
determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay.
RESULTS: TFT systemic exposure in plasma increased dose-dependently. The tumor 
growth rate and body weight gain decreased dose-dependently, but TFT 
concentrations in the DNA of tumor tissues and white blood cells increased 
dose-dependently. TFT inhibited colony formation of bone marrow cells in a 
concentration-dependent manner.
CONCLUSIONS: A significant relationship between systemic exposure of TFT and 
pharmacological effects including the antitumor activity and body weight change 
was well explained by the TFT incorporation into DNA. TFT inhibited 
proliferations of mouse bone marrow cells and human colorectal carcinoma cells 
implanted to nude mice dose-dependently. The highest tolerable TFT exposure 
provides the highest antitumor activity, and the hematological toxicity may 
serve as a potential surrogate indicator of TAS-102 efficacy.