title: Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.
abstract: TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients.
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okabe
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Fujioka
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tokushima Research Center, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakagawa
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tokushima Research Center, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yokogawa
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Oguchi
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Osada
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kazuno
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsuo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004273:DNA, Neoplasm / Q000235:genetics*; D004338:Drug Combinations; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage* / Q000378:metabolism; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine