Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity |
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Authors: | Sakamoto Etsuko Tsukioka Sayaka Oie Shinji Kobunai Takashi Tsujimoto Hiroaki Sakamoto Kazuki Okayama Yoshihiro Sugimoto Yoshikazu Oka Toshinori Fukushima Masakazu Oka Tatsuzo |
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Institution: | a Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan b Personalized Medicine Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno Hiraishi, Kawauchi-cho Tokushima 771-0194, Japan |
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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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Keywords: | LV 5-FU FPGS GGH Leucovorin Folylpolyglutamate synthase γ-Glutamyl hydrolase 5-Fluorouracil |
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