Skip to main content
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Small Molecule Therapeutics

TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy

Wakako Yano, Tatsushi Yokogawa, Takeshi Wakasa, Keisuke Yamamura, Akio Fujioka, Kunihiro Yoshisue, Eiji Matsushima, Seiji Miyahara, Hitoshi Miyakoshi, Junko Taguchi, Khoon Tee Chong, Yayoi Takao, Masayoshi Fukuoka and Kenichi Matsuo
Wakako Yano
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tatsushi Yokogawa
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
2Business Development Department, Taiho Pharmaceutical Co., Ltd., Kandanishiki-cho, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: matsuken@taiho.co.jp
Takeshi Wakasa
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keisuke Yamamura
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akio Fujioka
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kunihiro Yoshisue
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eiji Matsushima
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Seiji Miyahara
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hitoshi Miyakoshi
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Junko Taguchi
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Khoon Tee Chong
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yayoi Takao
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masayoshi Fukuoka
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenichi Matsuo
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: matsuken@taiho.co.jp
DOI: 10.1158/1535-7163.MCT-17-0911 Published August 2018
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Additional Files
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1.

    Concept of dual inhibition with combination treatment of capecitabine and TAS-114. Combination with TAS-114 can reduce the maximum tolerated dose of capecitabine by DPD inhibition, and it significantly enhances the antitumor efficacy through dUTPase inhibition. TAS-114 improves the therapeutic window of capecitabine.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    TAS-114, a novel dual dUTPase/DPD inhibitor, and its enzyme inhibition kinetics and selectivity in nucleotide hydrolysis. A, Chemical structure of TAS-114. B, X-ray cocrystal structure of TAS-114 with human dUTPase (PDB code: 5H4J). C, Effects of TAS-114 on hydrolysis of nucleotide triphosphates in a HeLa cell extract. Substrates (TTP, UTP, dCTP, and dUTP) were mixed at 1 μmol/L with a HeLa cell extract and incubated for 30 minutes at 37°C. The inhibitory activity of TAS-114 at 10 μmol/L was determined as the percent decrease in substrates following treatment with the cell extract. Triphosphate (TP), diphosphate (DP), monophosphate (MP), and nucleoside (Ns).

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3.

    TAS-114 enhances the cytotoxicity of a TS inhibitor via dUTPase inhibition. A, TAS-114 enhanced FdUrd, but not paclitaxel-induced cytotoxicity in various cancer cell lines. Cell growth inhibition was determined by crystal violet staining. The cells were treated with FdUrd and paclitaxel in combination with TAS-114 at 10 μmol/L for 72 hours. B, Comparison of the effects of a dual dUTPase/DPD inhibitor (TAS-114) and a potent DPD inhibitor (gimeracil) on HeLa cells. The cells were treated with 5-FU, TAS-114 at 10 μmol/L, and gimeracil at 10 μmol/L for 72 hours, and cell growth inhibition was determined by crystal violet staining.

  • Figure 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 4.

    Efficacy and toxicity of capecitabine and TAS-114 combination. A, Efficacy and toxicity titration study of capecitabine and TAS-114 combination. Dose responses to combined administration of TAS-114 with capecitabine in nude mice bearing MX-1 tumors. The mice (n = 5 per group) were orally administered capecitabine and/or TAS-114 at various doses from day 1 to day 14. Each value in the cell is the tumor growth inhibition rate (%) on day 15. *, P < 0.05 and **, P < 0.01 versus control. #, P < 0.05 and ##, P < 0.01 versus capecitabine, 539 mg/kg/day (maximum tolerated dose of capecitabine alone). B, Antitumor efficacy and toxicity of capecitabine plus a dual inhibitor of dUTPase and DPD (TAS-114) versus a selective DPD inhibitor (gimeracil) in an MX-1 xenograft mouse model. Nude mice bearing MX-1 tumors (n = 5 per group) were orally administered capecitabine at 240, 539, and 809 mg/kg/day, TAS-114 at 600 mg/kg/day, and gimeracil at 0.7 mg/kg/day from day 1 to day 14. Data are presented as the mean ± SD. **, P < 0.01 versus control. #, P < 0.05 and ##, P < 0.01 versus capecitabine (539 mg/kg/day).

  • Figure 5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 5.

    Antitumor efficacy of the S-1 and TAS-114 combination in a xenograft model. Antitumor efficacy (A) and toxicity (B) of S-1 in combination with TAS-114 in an MX-1 xenograft rat model. Nude rats bearing MX-1 tumors (n = 5 per group) were orally administered S-1 at 15 mg/kg/day and TAS-114 at 75, 300, and 1,000 mg/kg/day from day 1 to day 14. Data are presented as the mean ± SD. **, P < 0.01 versus control. ##, P < 0.01 versus S-1 alone. B, Body weight change in the rats corresponding to A. C, Pharmacodynamic study in rats. Nude rats bearing MX-1 tumors (n = 5 per group) were orally administered S-1 at 15 mg/kg and TAS-114 at 75, 300, and 1,000 mg/kg. Tumor samples were collected 4 hours after oral administration. Data are presented as the mean ± SD. D, dUMP, FdUMP, and free TS in tumor and normal tissues after administration of S-1 to rats. S-1 was orally administered at a dose of 18 mg/kg to nude rats bearing MX-1 tumors (n = 3 per group). Tumor and normal tissue samples were collected from nontreated and treated rats 2 hours after oral administration. Data are presented as the mean ± SD.

Tables

  • Figures
  • Additional Files
  • Table 1.

    Pharmacokinetic and pharmacodynamic studies of capecitabine in combination with TAS-114 or gimeracil

    PlasmaTumor
    5-FUTAS-114Free FdUMPdUMPFree TS (pmol/mg protein)
    2 hours after administration
    DrugsDose (mg/kg)AUC0-6 (ng·h/mL)AUC0-6 (ng·h/mL)AUClast (pmol·h/g tissue)AUClast (nmol·h/g tissue)MeanSD
    Nontreatment—————0.7390.086
    Capecitabine240109—2,8994300.0500.006
    539521—7,1175260.0220.005
    8091,161—12,5485940.0130.005
    Capecitabine/TAS-114240/384505,4152,0922780.0420.011
    240/1501,34528,3621,3461720.0660.009
    240/6001,91781,046789690.0570.013
    Capecitabine/gimeracil240/0.182,247—4,2734540.0330.016
    240/0.72,469—6,2285440.0220.006
    • NOTE: Plasma and tumor tissues were collected at 0.5, 1, 2, 4, and 6 hours after drug administration from three nude mice with MX-1 (human breast cancer) at each sampling point per group.

Additional Files

  • Figures
  • Tables
  • Supplementary Data

    • Table S1 - X-ray crystallography data and refinement statistics
    • Table S2 - Cytotoxicity effects of 5-FU, FdUrd, and paclitaxel in combination with TAS-114 in various human cancer cell lines
    • Table S3 - Median survival times in a CFPAC-1 peritoneal dissemination model after S-1, TAS-114, or S-1 and TAS-114 combination treatment
    • Figure S1 - Detail description of TAS-114 synthesis
    • Figure S2 - Enzyme kinetic analysis of human dUTPase inhibition by TAS-114 and calculation of Km and Ki values
    • Figure S3 - TAS-114 possesses moderate DPD inhibitory activity, and its inhibition mode is reversible
    • Figure S4 - Expression levels of dUTPase in various tumor xenografts and antitumor efficacy of S-1 and TAS-114 combination in various xenograft models
    • Figure S5 - Pharmacokinetic analysis of S-1 and TAS-114 combination in SD rats
PreviousNext
Back to top
Molecular Cancer Therapeutics: 17 (8)
August 2018
Volume 17, Issue 8
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy
Wakako Yano, Tatsushi Yokogawa, Takeshi Wakasa, Keisuke Yamamura, Akio Fujioka, Kunihiro Yoshisue, Eiji Matsushima, Seiji Miyahara, Hitoshi Miyakoshi, Junko Taguchi, Khoon Tee Chong, Yayoi Takao, Masayoshi Fukuoka and Kenichi Matsuo
Mol Cancer Ther August 1 2018 (17) (8) 1683-1693; DOI: 10.1158/1535-7163.MCT-17-0911

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy
Wakako Yano, Tatsushi Yokogawa, Takeshi Wakasa, Keisuke Yamamura, Akio Fujioka, Kunihiro Yoshisue, Eiji Matsushima, Seiji Miyahara, Hitoshi Miyakoshi, Junko Taguchi, Khoon Tee Chong, Yayoi Takao, Masayoshi Fukuoka and Kenichi Matsuo
Mol Cancer Ther August 1 2018 (17) (8) 1683-1693; DOI: 10.1158/1535-7163.MCT-17-0911
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Efficacy of Rigosertib in Rhabdomyosarcoma and Neuroblastoma
  • Combination of AZD0364 and Selumetinib in KRAS-Mutant NSCLC
  • eFT226, a Selective Inhibitor of eIF4A-Mediated Translation
Show more Small Molecule Therapeutics
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About MCT

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement