title: Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse.
abstract: OBJECTIVE
  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.
authors.affiliation: Pharmacokinetics Research Laboratories, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan, f-yamashita@taiho.co.jp.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yamashita
authors.forename: Ikumi
authors.initials: I
authors.lastname: Komoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Oka
authors.forename: Keizo
authors.initials: K
authors.lastname: Kuwata
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakagawa
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yoshisue
authors.forename: Masato
authors.initials: M
authors.lastname: Chiba
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism*; D004338:Drug Combinations; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008819:Mice, Nude; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine