An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA.
TAS-102 is a combination drug consisting of alpha,alpha,alpha-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). FTD is converted to F3TMP by thymidine kinase and inhibits the thymidylate synthetase (TS) activity by binding to TS. In addition, FTD triphosphate form, F3TTP is incorporated into DNA, which leads to cytocidal effects. Therefore, the incorporation of FTD into DNA is expected to be an important factor, discriminating it from 5-FU showing TS inhibitory activity as their main mechanism of action. To assess a clinically more effective regimen protocol, the intracellular metabolism and the incorporation of FTD into DNA were investigated using human cancer cell lines in vitro and in vivo. FTD was incorporated into DNA in a time-dependent manner, but not in a concentration-dependent manner. FTD was the most efficiently incorporated into DNA after treatment with a several-micro molar level of FTD for around 8 h. The intracellular F3TTP was rapidly eliminated from tumor cells, as soon as FTD was washed out from the culture medium, whereas the FTD incorporated into DNA was retained by 80% or more even at 24 h after a washing-out procedure. When TAS-102 was administered into tumor-bearing mice once daily or three times daily at 3-h intervals at a dose of 150 mg/kg/day for one or 3 consecutive days, incorporation of FTD into tumor DNA by divided dosing significantly higher than that of single dosing. Based on our findings, the antitumor effects of TAS-102 against 3 different human cancer cell xenografts into mice were examined. The divided daily dosing resulted in enhancement of the antitumor effects of TAS-102 without any additional side effects. It is concluded that multiple daily dosing may result in better clinical benefits of TAS-102, when compared with single daily dosing and TAS-102 is a promising candidate for not only FU-sensitive but also FU-resistant cancer patients.
Emura
Tomohiro
T
Cancer Research Laboratories, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno-city, Saitama 357-8527, Japan. t-emura@taiho.co.jp
Nakagawa
Fumio
F
Fujioka
Akio
A
Ohshimo
Hideyuki
H
Yokogawa
Tatsushi
T
Okabe
Hiroyuki
H
Kitazato
Kenji
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D013274:Stomach Neoplasms / Q000188:drug therapy; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014271:Trifluridine / Q000493:pharmacokinetics / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004247:DNA; D013939:Thymidine Phosphorylase; D014271:Trifluridine