Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity.
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 gamma-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.
Sakamoto
Etsuko
E
Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan.
Tsukioka
Sayaka
S
Oie
Shinji
S
Kobunai
Takashi
T
Tsujimoto
Hiroaki
H
Sakamoto
Kazuki
K
Okayama
Yoshihiro
Y
Sugimoto
Yoshikazu
Y
Oka
Toshinori
T
Fukushima
Masakazu
M
Oka
Tatsuzo
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010453:Peptide Synthases / Q000378:metabolism*; D016896:Treatment Outcome; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism*
D000970:Antineoplastic Agents; D011623:gamma-Glutamyl Hydrolase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D002955:Leucovorin; D005472:Fluorouracil