Article Figures & Data
Figures
- 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.
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.
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.
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.
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
- Table 1.
Pharmacokinetic and pharmacodynamic studies of capecitabine in combination with TAS-114 or gimeracil
Plasma Tumor 5-FU TAS-114 Free FdUMP dUMP Free TS (pmol/mg protein) 2 hours after administration Drugs Dose (mg/kg) AUC0-6 (ng·h/mL) AUC0-6 (ng·h/mL) AUClast (pmol·h/g tissue) AUClast (nmol·h/g tissue) Mean SD Nontreatment — — — — — 0.739 0.086 Capecitabine 240 109 — 2,899 430 0.050 0.006 539 521 — 7,117 526 0.022 0.005 809 1,161 — 12,548 594 0.013 0.005 Capecitabine/TAS-114 240/38 450 5,415 2,092 278 0.042 0.011 240/150 1,345 28,362 1,346 172 0.066 0.009 240/600 1,917 81,046 789 69 0.057 0.013 Capecitabine/gimeracil 240/0.18 2,247 — 4,273 454 0.033 0.016 240/0.7 2,469 — 6,228 544 0.022 0.006 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.
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
Volume 17, Issue 8
