Oral fluoropyrimidine S-1 combined with leucovorin is a promising therapy for colorectal cancer: Evidence from a xenograft model of folate-depleted mice

Sayaka Tsukioka, Junji Uchida, Hiroaki Tsujimoto, Fumio Nakagawa, Yoshikazu Sugimoto, Toshinori Oka, Mamoru Kiniwa

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)393-398
Number of pages6
JournalMolecular Medicine Reports
Volume2
Issue number3
DOIs
Publication statusPublished - 2009 Aug 31
Externally publishedYes

Keywords

  • 5-fluorouracil
  • Leucovorin
  • Reduced folate
  • S-1
  • Thymidylate synthase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

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