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Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks

  • Authors:
    • Norihiko Suzuki
    • Fumio Nakagawa
    • Mamoru Nukatsuka
    • Masakazu Fukushima
  • View Affiliations / Copyright

    Affiliations: Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan
  • Pages: 393-397
    |
    Published online on: March 21, 2011
       https://doi.org/10.3892/etm.2011.244
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Abstract

TAS-102 is an oral anticancer drug composed of trifluorothymidine (TFT) and TPI (an inhibitor of thymidine phosphorylase that strongly inhibits the biodegradation of TFT). Similar to 5-fluorouracil (5FU) and 5-fluoro-2'-deoxyuridine (FdUrd), TFT also inhibits thymidylate synthase (TS), a rate-limiting enzyme of DNA biosynthesis, and is incorporated into DNA. TFT exhibits an anticancer effect on colorectal cancer cells that have acquired 5FU and/or FdUrd resistance as a result of the overexpression of TS. Therefore, we examined the mode of action of TFT-induced DNA damage after its incorporation into DNA. When HeLa cells were treated with TFT, the number of ring-open aldehyde forms at apurinic/apyrimidinic sites increased in a dose-dependent manner, although we previously reported that no detectable excisions of TFT paired to adenine were observed using uracil DNA glycosylases, thymine DNA glycosylase or methyl-CpG binding domain 4 and HeLa whole cell extracts. To investigate the functional mechanism of TFT-induced DNA damage, we measured the phosphorylation of ATR, ATM, BRCA2, chk1 and chk2 in nuclear extracts of HeLa cells after 0, 24, 48 or 72 h of exposure to an IC50 concentration of TFT, FdUrd or 5FU using Western blot analysis or an enzyme-linked immuno-sorbent assay (ELISA). Unlike FdUrd and 5FU, TFT resulted in an earlier phosphorylation of ATR and chk1 proteins after only 24 h of exposure, while phosphorylated ATM, BRCA2 and chk2 proteins were detected after more than 48 h of exposure to TFT. These results suggest that TFT causes single-strand breaks followed by double-strand breaks in the DNA of TFT-treated cells. TFT (as TAS-102) showed a more potent antitumor activity than oral 5FU on CO-3 colon cancer xenografts in mice, and such antitumor potency was supported by the increased number of double-strand breaks occurring after single-strand breaks in the DNA of the TFT-treated tumors. These results suggest that TFT causes single-strand breaks after its incorporation into DNA followed by double-strand breaks, resulting in DNA damage. This effect of TFT on DNA may explain its potent anticancer activity in cancer therapy.
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1. 

Heidelberger C, Parsons DG and Remy DC: Syntheses of 5-trifluoromethyluracil and 5-trifluoromethyl-2′-deoxyuridine. J Med Chem. 7:1–5. 1964.

2. 

Bresnick E and Wiliams SS: Effects of 5-trifluoromethyldeoxy-uridine upon deoxythymidine kinase. Biochem Pharmacol. 16:503–507. 1967. View Article : Google Scholar : PubMed/NCBI

3. 

Reyers P and Heidelberger C: Fluorinated pyrimidines: XXVI. Mammalian thymidylate synthetase: its mechanism of action and inhibition by fluorinated nucleotides. Mol Pharmacol. 1:14–30. 1965.

4. 

Eckstein JW, Foster PG, Finer-Moore J, Wataya Y and Santi DV: Mechanism-based inhibition of thymidylate synthase by 5-(trifluoromethyl)-2′-deoxyuridine 5′-monophosphate. Biochemistry. 3:15086–15094. 1994.PubMed/NCBI

5. 

Umeda M and Heidelberger C: Comparative studies of fluorinated pyrimidines with various cell lines. Cancer Res. 28:2529–2538. 1968.PubMed/NCBI

6. 

Murakami Y, Kazuno H, Emura T, Tsujimoto H, Suzuki N and Fukushima M: Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells. Int J Oncol. 17:277–283. 2000.PubMed/NCBI

7. 

Emura T, Nakagawa F, Fujioka A, Ohshimo H, Yokogawa T, Okabe H and Kitazato K: An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA. Int J Mol Med. 13:249–255. 2004.PubMed/NCBI

8. 

Emura T, Suzuki N, Yamaguchi M, Ohshimo H and Fukushima M: A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol. 25:571–578. 2004.

9. 

Suzuki N, Emura T and Fukushima M: Mode of action of trifluorothymidine (TFT) against DNA replication and repair enzymes. Int J Oncol. (In press).

10. 

Nakamura J, Walger VE, Upton PB, Chiang SY, Kow YW and Swenberg JA: Highly sensitive apurinic/apyrimidinic site assay can detect spontaneous and chemically induced depurination under physiological conditions. Cancer Res. 58:222–225. 1998.

11. 

Nishikawa T, Munshi A, Story MD, Ismail S, Stevens C, Chada S and Meyn RE: Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells. Oncogene. 16:7125–7131. 2004. View Article : Google Scholar : PubMed/NCBI

12. 

Hartman KY and Heidelberger C: Studies on fluorinated pyrimidines: XIII. Inhibition of thymidylate synthase. J Biol Chem. 236:3006–3013. 1961.PubMed/NCBI

13. 

Santi DV and McHenry CS: 5-Fluoro-2′-deoxyuridinylate: covalent complex with thymidylate synthase. Proc Natl Acad Sci USA. 69:1855–1857. 1972.

14. 

Glazer RI and Lloyd LS: Association of cell lethality with incorporation of 5-fluorouracil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture. Mol Pharmacol. 21:468–473. 1982.PubMed/NCBI

15. 

Greenhalgh DA and Parish JH: Effect of 5-fluorouracil on cytotoxicity and RNA metabolism in human colonic carcinoma cells. Cancer Chemother Pharmacol. 25:37–44. 1989. View Article : Google Scholar : PubMed/NCBI

16. 

Rogers WI, Hartman AC, Palm PE, Okstein C and Kensler CJ: The fate of 5-trifluoromethyl-2′-deoxyuridine in monkeys, dogs, mice, and tumor-bearing mice. Cancer Res. 29:953–961. 1969.PubMed/NCBI

17. 

Dexter DL, Wolberg WH, Ansfield FJ, Helson L and Heidelberger C: The clinical pharmacology of 5-trifluoromethyl-2′-deoxyuridine. Cancer Res. 32:247–53. 1972.

18. 

Suzuki N and Fukushima M: Simple and rapid enzymatic method for the synthesis of single-strand oligonucleotides containing trifluorothymidine. Nucleosides Nucleotides Nucleic Acids. 29:896–904. 2010. View Article : Google Scholar

19. 

Bijnsdorp IV, Kruyt FA, Gokoel S, Fukushima M and Peters GJ: Synergistic interaction between trifluorothymidine and docetaxel is sequence dependent. Cancer Sci. 99:2302–2308. 2008. View Article : Google Scholar : PubMed/NCBI

20. 

Backus HH, Pinedo HM, Wouters D, Kuiper CM, Jansen G, van Groeningen CJ and Peters GJ: Differences in the induction of DNA damage, cell cycle arrest, and cell death by 5-fluorouracil and antifolates. Oncol Res. 12:231–239. 2000.PubMed/NCBI

21. 

Brown EJ and Baltimore D: Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17:615–628. 2003. View Article : Google Scholar : PubMed/NCBI

22. 

Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K and Takeda S: The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J. 19:463–471. 2000. View Article : Google Scholar : PubMed/NCBI

23. 

Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, Goodarzi AA, Krempler A, Jeggo PA and Löbrich M: ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J. 28:3413–3427. 2009. View Article : Google Scholar : PubMed/NCBI

24. 

Branzei D and Foiani M: Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 9:297–308. 2008. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Suzuki N, Nakagawa F, Nukatsuka M and Fukushima M: Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks. Exp Ther Med 2: 393-397, 2011.
APA
Suzuki, N., Nakagawa, F., Nukatsuka, M., & Fukushima, M. (2011). Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks. Experimental and Therapeutic Medicine, 2, 393-397. https://doi.org/10.3892/etm.2011.244
MLA
Suzuki, N., Nakagawa, F., Nukatsuka, M., Fukushima, M."Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks". Experimental and Therapeutic Medicine 2.3 (2011): 393-397.
Chicago
Suzuki, N., Nakagawa, F., Nukatsuka, M., Fukushima, M."Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks". Experimental and Therapeutic Medicine 2, no. 3 (2011): 393-397. https://doi.org/10.3892/etm.2011.244
Copy and paste a formatted citation
x
Spandidos Publications style
Suzuki N, Nakagawa F, Nukatsuka M and Fukushima M: Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks. Exp Ther Med 2: 393-397, 2011.
APA
Suzuki, N., Nakagawa, F., Nukatsuka, M., & Fukushima, M. (2011). Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks. Experimental and Therapeutic Medicine, 2, 393-397. https://doi.org/10.3892/etm.2011.244
MLA
Suzuki, N., Nakagawa, F., Nukatsuka, M., Fukushima, M."Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks". Experimental and Therapeutic Medicine 2.3 (2011): 393-397.
Chicago
Suzuki, N., Nakagawa, F., Nukatsuka, M., Fukushima, M."Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks". Experimental and Therapeutic Medicine 2, no. 3 (2011): 393-397. https://doi.org/10.3892/etm.2011.244
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