TY - JOUR
T1 - Oral fluoropyrimidine S-1 combined with leucovorin is a promising therapy for colorectal cancer
T2 - Evidence from a xenograft model of folate-depleted mice
AU - Tsukioka, Sayaka
AU - Uchida, Junji
AU - Tsujimoto, Hiroaki
AU - Nakagawa, Fumio
AU - Sugimoto, Yoshikazu
AU - Oka, Toshinori
AU - Kiniwa, Mamoru
PY - 2009/8/31
Y1 - 2009/8/31
N2 - The oral fluoropyrimidine S-1 has marked efficacy in treating metastatic colorectal cancer patients. In the present study, we explored the therapeutic potential of combined in vivo treatment in the human colon cancer cell lines COL-1, KM12C and KM20C with consecutive oral S-1 and leucovorin (LV) in 2-week therapeutic periods. This combination had increased anticancer activity compared to S-1 alone in the xenografts tested. Moreover, oral S-1/LV treatment showed a more potent anticancer effect on COL-1 xenografts than infusional 5-fluorouracil (5-FU)/LV, with comparable loss of body weight. The reduced folate level in the tumors was initially low, but rapidly rose and persisted for a long period of over 24 h after a single LV administration. This resulted in the formation of much higher levels of the ternary complex with thymidylate synthase (TS) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) derived from 5-FU, leading to a prolonged inhibition of TS activity in combined administration with oral S-1. These results suggest that the co-administration of LV with S-1 might improve therapeutic efficacy in the treatment of colorectal cancer patients.
AB - The oral fluoropyrimidine S-1 has marked efficacy in treating metastatic colorectal cancer patients. In the present study, we explored the therapeutic potential of combined in vivo treatment in the human colon cancer cell lines COL-1, KM12C and KM20C with consecutive oral S-1 and leucovorin (LV) in 2-week therapeutic periods. This combination had increased anticancer activity compared to S-1 alone in the xenografts tested. Moreover, oral S-1/LV treatment showed a more potent anticancer effect on COL-1 xenografts than infusional 5-fluorouracil (5-FU)/LV, with comparable loss of body weight. The reduced folate level in the tumors was initially low, but rapidly rose and persisted for a long period of over 24 h after a single LV administration. This resulted in the formation of much higher levels of the ternary complex with thymidylate synthase (TS) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) derived from 5-FU, leading to a prolonged inhibition of TS activity in combined administration with oral S-1. These results suggest that the co-administration of LV with S-1 might improve therapeutic efficacy in the treatment of colorectal cancer patients.
KW - 5-fluorouracil
KW - Leucovorin
KW - Reduced folate
KW - S-1
KW - Thymidylate synthase
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UR - http://www.scopus.com/inward/citedby.url?scp=69249092231&partnerID=8YFLogxK
U2 - 10.3892/mmr-00000111
DO - 10.3892/mmr-00000111
M3 - Article
C2 - 21475840
AN - SCOPUS:69249092231
VL - 2
SP - 393
EP - 398
JO - Molecular Medicine Reports
JF - Molecular Medicine Reports
SN - 1791-2997
IS - 3
ER -