Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity

Etsuko Sakamoto, Sayaka Tsukioka, Shinji Oie, Takashi Kobunai, Hiroaki Tsujimoto, Kazuki Sakamoto, Yoshihiro Okayama, Yoshikazu Sugimoto, Toshinori Oka, Masakazu Fukushima, Tatsuzo Oka

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Although 5-fluorouracil (5-FU) plus leucovorin (LV) is a standard chemotherapy regimen for colorectal cancer, the factors that determine the LV-mediated enhancement of the antitumor activity of 5-FU have remained unknown. We investigated the roles of folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH), which are the main enzymes involved in folate metabolism, in the effect of LV. LV enhanced the anticancer activity of 5-FU and the level of reduced folate in human colon cancer cells. Small-interfering RNA (siRNA) transfected into DLD-1 cells to downregulate FPGS reduced the basal level of reduced folate, the folate level after LV treatment, and the enhancement of 5-fluoro-2′-deoxyuridine (FdUrd)-induced cytotoxicity elicited by LV. By contrast, the downregulation of GGH by siRNA increased cellular sensitivity to FdUrd combined with LV. These results suggest that FPGS and GGH expression levels in tumors are determinants of the efficacy of LV in enhancing the antitumor activity of 5-FU.

Original languageEnglish
Pages (from-to)801-807
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume365
Issue number4
DOIs
Publication statusPublished - 2008 Jan 25
Externally publishedYes

Fingerprint

Leucovorin
Hydrolases
Fluorouracil
Folic Acid
Small Interfering RNA
Down-Regulation
Chemotherapy
folylpolyglutamate synthetase
Cytotoxicity
Metabolism
Colonic Neoplasms
Tumors
Colorectal Neoplasms
Cells
Drug Therapy
Enzymes

Keywords

  • γ-Glutamyl hydrolase
  • 5-Fluorouracil
  • 5-FU
  • Folylpolyglutamate synthase
  • FPGS
  • GGH
  • Leucovorin
  • LV

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity. / Sakamoto, Etsuko; Tsukioka, Sayaka; Oie, Shinji; Kobunai, Takashi; Tsujimoto, Hiroaki; Sakamoto, Kazuki; Okayama, Yoshihiro; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu; Oka, Tatsuzo.

In: Biochemical and Biophysical Research Communications, Vol. 365, No. 4, 25.01.2008, p. 801-807.

Research output: Contribution to journalArticle

Sakamoto, E, Tsukioka, S, Oie, S, Kobunai, T, Tsujimoto, H, Sakamoto, K, Okayama, Y, Sugimoto, Y, Oka, T, Fukushima, M & Oka, T 2008, 'Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity', Biochemical and Biophysical Research Communications, vol. 365, no. 4, pp. 801-807. https://doi.org/10.1016/j.bbrc.2007.11.043
Sakamoto, Etsuko ; Tsukioka, Sayaka ; Oie, Shinji ; Kobunai, Takashi ; Tsujimoto, Hiroaki ; Sakamoto, Kazuki ; Okayama, Yoshihiro ; Sugimoto, Yoshikazu ; Oka, Toshinori ; Fukushima, Masakazu ; Oka, Tatsuzo. / Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity. In: Biochemical and Biophysical Research Communications. 2008 ; Vol. 365, No. 4. pp. 801-807.
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