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Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase

  • Authors:
    • Hiroaki Tsujimoto
    • Sayaka Tsukioka
    • Satoru Ono
    • Etsuko Sakamoto
    • Kazuki Sakamoto
    • Kohji Tsuta
    • Fumio Nakagawa
    • Hitoshi Saito
    • Junji Uchida
    • Mamoru Kiniwa
    • Masakazu Fukushima
  • View Affiliations / Copyright

    Affiliations: Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan
  • Pages: 973-980
    |
    Published online on: September 17, 2010
       https://doi.org/10.3892/ol.2010.172
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Abstract

The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or 5-FU prodrugs in low folate diet-fed nude mice using human colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55-79% inhibition of tumor growth among 11 types of colorectal tumor xenograft, whereas UFT alone showed 23-67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in tumors. To investigate the reason for the higher efficacy of UFT/LV on colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated tumors were noted. Our results indicate that a combined therapy of UFT with LV may contribute to the treatment of colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT.
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Copy and paste a formatted citation
Spandidos Publications style
Tsujimoto H, Tsukioka S, Ono S, Sakamoto E, Sakamoto K, Tsuta K, Nakagawa F, Saito H, Uchida J, Kiniwa M, Kiniwa M, et al: Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncol Lett 1: 973-980, 2010.
APA
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K. ... Fukushima, M. (2010). Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncology Letters, 1, 973-980. https://doi.org/10.3892/ol.2010.172
MLA
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K., Nakagawa, F., Saito, H., Uchida, J., Kiniwa, M., Fukushima, M."Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase". Oncology Letters 1.6 (2010): 973-980.
Chicago
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K., Nakagawa, F., Saito, H., Uchida, J., Kiniwa, M., Fukushima, M."Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase". Oncology Letters 1, no. 6 (2010): 973-980. https://doi.org/10.3892/ol.2010.172
Copy and paste a formatted citation
x
Spandidos Publications style
Tsujimoto H, Tsukioka S, Ono S, Sakamoto E, Sakamoto K, Tsuta K, Nakagawa F, Saito H, Uchida J, Kiniwa M, Kiniwa M, et al: Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncol Lett 1: 973-980, 2010.
APA
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K. ... Fukushima, M. (2010). Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncology Letters, 1, 973-980. https://doi.org/10.3892/ol.2010.172
MLA
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K., Nakagawa, F., Saito, H., Uchida, J., Kiniwa, M., Fukushima, M."Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase". Oncology Letters 1.6 (2010): 973-980.
Chicago
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K., Nakagawa, F., Saito, H., Uchida, J., Kiniwa, M., Fukushima, M."Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase". Oncology Letters 1, no. 6 (2010): 973-980. https://doi.org/10.3892/ol.2010.172
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