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

doi:10.1016/j.bbrc.2007.11.043

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 journal › Article › peer-review

27 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 language	English
Pages (from-to)	801-807
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	365
Issue number	4
DOIs	https://doi.org/10.1016/j.bbrc.2007.11.043
Publication status	Published - 2008 Jan 25
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2007.11.043

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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, 365(4), 801-807. https://doi.org/10.1016/j.bbrc.2007.11.043

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

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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.",

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AU - Kobunai, Takashi

AU - Tsujimoto, Hiroaki

AU - Sakamoto, Kazuki

AU - Okayama, Yoshihiro

AU - Sugimoto, Yoshikazu

AU - Oka, Toshinori

AU - Fukushima, Masakazu

AU - Oka, Tatsuzo

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N2 - 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.

AB - 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.

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KW - 5-Fluorouracil

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KW - LV

KW - Leucovorin

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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