Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer

Hiroki Ide, Eiji Kikuchi, Masanori Hasegawa, Seiya Hattori, Yota Yasumizu, Akira Miyajima, Mototsugu Oya

Research output: Contribution to journalArticle

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Abstract

Thymidylate synthase (TS), a target enzyme of 5-fluorouracil (5-FU), is significantly associated with prognosis in various cancers. Recently, it has been reported that S-1, a novel 5-FU-based agent has an effect on bladder cancer. However, in cells with high TS level, S-1 did not have significant effects. Therefore, we examined whether down-regulation of TS enhanced effects of S-1 in them. First, we measured TS level in an aggressive bladder cancer cell line, KU-19-19 by enzyme-linked immunosorbent assay (ELISA) and evaluated its sensitivity to 5-FU using a small interfering RNA (siRNA) for TS. Next, we measured TS mRNA after exposure to various agents. Finally, we evaluated enhancement of cytotoxicity of S-1 by CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) which down-regulated TS in in vivo study. The median TS and dihydropyrimidine dehydrogenase (DPD) level was 53.3 ng/mg and 80.3 ng/mg in KU-19-19 cells, respectively. The 5-FU treatment in KU-19-19 cells transfected with siRNA for TS gene (TYMS) inhibited cell growth more significantly than that for nontargeting control. Down-regulation of TS was observed after exposure to SN-38 (7-ethyl-10-hydroxycamptothecin) in a dose-dependent manner. The combination treatment of 5-FU and SN-38 significantly inhibited cell growth, as compared to the single treatment. Meanwhile, in cells transfected with siRNA for TYMS, neither an additive nor a synergistic effect was observed. Also, combined S-1 and CPT-11 dramatically inhibited tumor growth, compared to S-1 or CPT-11 alone in in vivo study. In conclusion, CPT-11 down-regulated TS level and enhanced the effect of S-1. Thus, the combination therapy with S-1 and CPT-11 might be a novel modality for bladder cancer, even with high TS level.

Original languageEnglish
Pages (from-to)488-495
Number of pages8
JournalCancer Medicine
Volume2
Issue number4
DOIs
Publication statusPublished - 2013

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irinotecan
Thymidylate Synthase
Urinary Bladder Neoplasms
Down-Regulation
Fluorouracil
Therapeutics
Small Interfering RNA
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Radiology Nuclear Medicine and imaging

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Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer. / Ide, Hiroki; Kikuchi, Eiji; Hasegawa, Masanori; Hattori, Seiya; Yasumizu, Yota; Miyajima, Akira; Oya, Mototsugu.

In: Cancer Medicine, Vol. 2, No. 4, 2013, p. 488-495.

Research output: Contribution to journalArticle

Ide, H, Kikuchi, E, Hasegawa, M, Hattori, S, Yasumizu, Y, Miyajima, A & Oya, M 2013, 'Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer', Cancer Medicine, vol. 2, no. 4, pp. 488-495. https://doi.org/10.1002/cam4.95
Ide, Hiroki ; Kikuchi, Eiji ; Hasegawa, Masanori ; Hattori, Seiya ; Yasumizu, Yota ; Miyajima, Akira ; Oya, Mototsugu. / Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer. In: Cancer Medicine. 2013 ; Vol. 2, No. 4. pp. 488-495.
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