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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1989 Feb;80(2):173–181. doi: 10.1111/j.1349-7006.1989.tb02286.x

Antitumor Activity of BOF‐A2, a New 5‐Fluorouracil Derivative

Setsuro Fujii 1, Masakazu Fukushima 1, Yuji Shimamoto 1, Hideyuki Ohshimo 1, Takeshi Imaoka 1, Tetsuhiko Shirasaka 1
PMCID: PMC5917705  PMID: 2498252

Abstract

A compound containing both CNDP (3‐cyano‐2,6‐dihydroxypyridine), an inhibitor of 5‐fluorouracil (5‐FU) degradation, and EM‐FU (1‐ethoxymethyl‐5‐fluorouracil), a masked form of 5‐FU, was synthesized and named BOF‐A2 (3‐[3‐(6‐benzoyloxy‐3‐cyano‐2‐pyridyloxycarbonyl)benzoyl]‐1‐ethoxymethyl‐5‐fluorouracil). The antitumor activity of BOF‐A2 was investigated in sarcoma‐180‐bearing mice and Yoshida sarcoma‐bearing rats. The ED50 (the dose for 50% inhibition) values of BOF‐A2 were 25 mg/kg against sarcoma‐180 and 15 mg/kg against Yoshida sarcoma. In vitro studies showed that BOF‐A2 was rapidly degraded to EM‐FU and CNDP in homogenates of the liver and small intestine of mice and rats, and in sera of mice, rats and human, and the conversion of EM‐FU to 5‐FU occurred only in the microsomal fraction of rat liver in the presence of NADPH. After oral administration of BOF‐A2 at 15 mg/kg to Yoshida sarcoma‐bearing rats, BOF‐A2 was hydrolyzed to EM‐FU, CNDP and 5‐FU, and their maximum concentrations in the blood were 2000 ng/ml, 300 ng/ml and 40 ng/ml, respectively. Moreover when BOF‐A2 was given at the same dose to tumor‐bearing mice and rats, the 5‐FU levels in the tumor tissue increased much more than those in the blood and persisted for more than 8 h, whereas those in the blood decreased more rapidly. This accumulation and maintenance of a high level of 5‐FU in the tumor tissue are concluded to be related to the high antitumor activity of BOF‐A2.

Keywords: BOF‐A2, 5‐Fluorouracil derivative, Antitumor activity, Yoshida sarcoma, Sarcoma‐180

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REFERENCES

  • 1. ) Duschinsky , R. , Pleven , E. and Heidelberger , C.The synthesis of 5‐fluoropyrimidines . J. Am. Chem. Soc. , 79 , 4559 – 4560 ( 1957. ). [Google Scholar]
  • 2. ) Heidelberger , C. and Ansfield , F. J.Experimental and clinical use of fluorinated pyrimidines in cancer chemotherapy . Cancer Res. , 23 , 1226 – 1243 ( 1963. ). [PubMed] [Google Scholar]
  • 3. ) Seifert , P. , Baker , H. L. and Reed , M. L.Comparison of continuously infused 5‐fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma . Cancer , 36 , 123 – 128 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Shah , A. , MacDonald , W. , Goldie , J. , Gudauskas , G. and Brisebois , B.5‐FU infusion in advanced colorectal cancer: a comparison of three dose schedules . Cancer Treat. Rep. , 69 , 739 – 742 ( 1985. ). [PubMed] [Google Scholar]
  • 5. ) Caballero , G. A. , Ausman , R. K. and Quebbeman , E. J.Long‐term, ambulatory, continuous infusion of 5‐FU for the treatment of advanced adenocarcinomas . Cancer Treat. Rep. , 69 , 13 – 15 ( 1985. ). [PubMed] [Google Scholar]
  • 6. ) Bosch , L. , Harbers , E. and Heidelberger , C.Studies on fluorinated pyrimidines. V. Effects on nucleic acid metabolism in vitro . Cancer Res. , 18 , 335 – 343 ( 1958. ). [PubMed] [Google Scholar]
  • 7. ) Hartman , K. Y. and Heidelberger , C.Studies on fiuorinated pyrimidines. XIII. Inhibition of thymidylate synthase . J. Biol. Chem. , 236 , 3006 – 3018 ( 1961. ). [PubMed] [Google Scholar]
  • 8. ) Langenback , R. J. , Danenberg , P. V. and Heidelberger , C.Thymidylate synthase: mechanism of inhibition by 5‐fluoro‐2′‐deoxy‐uridylate . Biochem. Biophys. Res. Commun. , 48 , 1565 – 1571 ( 1972. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Santi , D. V. and McHenry , C. S.5‐Fluoro‐2′‐deoxyuridylate: covalent complex with thymidylate synthase . Proc. Natl. Acad. Sci. USA , 69 , 1855 – 1857 ( 1972. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Spears , C. P. , Shahinian , A. H. , Moran , R. G. , Heidelberger , C. and Corbett , T. H.In vivo kinetics of thymidylate synthase inhibition in 5‐fluorouracil‐sensitive and ‐resistant murine colon adenocarcinomas . Cancer Res. , 43 , 450 – 456 ( 1982. ). [PubMed] [Google Scholar]
  • 11. ) Spears , C. P. , Gustavsson , B. G. , Mitchell , M. S. , Spicer , D. , Berne , M. , Bernstein , L. and Danenberg , P. V.Thymidylate synthetase inhibition in malignant tumors and normal liver of patients given intravenous 5‐fluorouracil . Cancer Res. , 44 , 4144 – 4150 ( 1984. ). [PubMed] [Google Scholar]
  • 12. ) Wilkinson , D. S. , Tlsty , T. D. and Hanas , R. J.The inhibition of ribosomal RNA synthesis and maturation in Novikoff hepatoma cells by 5‐fluorouridine . Cancer Res. , 35 , 3014 – 3020 ( 1975. ). [PubMed] [Google Scholar]
  • 13. ) Nayak , R. , Nartin , D. , Stolfi , R. , Furth , J. and Spiegelman , S.Pyrimidine nucleosides enhance the anticancer activity of FU and augment its incorporation into nuclear RNA . Proc. Am. Assoc. Cancer Res. , 19 , 63 ( 1978. ). [Google Scholar]
  • 14. ) Ardalan , B. and Glazer , R.An update on the biochemistry of 5‐fluorouracil . Cancer Treat. Rev. , 8 , 157 – 167 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Dolnick , B. J. and Pink , J. J.5‐Fluorouracil modulation of dihydrofolate reductase RNA levels in methotrexate‐resistant KB cells . J. Biol. Chem. , 258 , 13299 – 13306 ( 1983. ). [PubMed] [Google Scholar]
  • 16. ) Carrico , C. K. and Glazer , R. I.Effects of 5‐fluorouracil on the synthesis and translation of polyadenylic acid‐containing RNA from regenerating rat liver . Cancer Res. , 39 , 3694 – 4701 ( 1979. ). [PubMed] [Google Scholar]
  • 17. ) Danenberg , P. V. , Heidelberger , C. , Mulkins , M. A. and Peterson , A. R.Incorporation of 5‐fluoro‐2′‐deoxyuridine into DNA of mammalian tumor cells . Biochem. Biophys. Res. Commun. , 102 , 654 – 658 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Major , P. P. , Egan , E. , Herrick , K. and Kufe , D. W.5‐Fluorouracil incorporation in DNA of human breast carcinoma cells . Cancer Res. , 42 , 3005 – 3009 ( 1982. ). [PubMed] [Google Scholar]
  • 19. ) Swayer , R. C. , Stolfi , R. L. , Martin , D. S. and Spiegelman , S.Incorporation of 5‐fluorouracil into murine bone marrow DNA in vivo . Cancer Res. , 44 , 1847 – 1851 ( 1984. ). [PubMed] [Google Scholar]
  • 20. ) Ikenaka , K. , Shirasaka , T. , Kitano , S. and Fujii , S.Effects of uracil on metabolism of 5‐fluorouracil in vitro . Gann , 70 , 353 – 359 ( 1979. ). [PubMed] [Google Scholar]
  • 21. ) Heggie , G. D. , Sommadossi , J‐P. , Cross , D. S. , Huster , W. J. and Diasio , R. B.Clinical pharmacokinetics of 5‐fluorouracil and its metabolites in plasma, urine, and bile . Cancer Res. , 47 , 2203 – 2206 ( 1987. ). [PubMed] [Google Scholar]
  • 22. ) Hull , W. E. , Port , R. E. , Harrmann , R. , Britsch , B. and Kunz , W.Metabolite of 5‐fluorouracil in plasma and urine, as monitored by 19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment . Cancer Res. , 48 , 1680 – 1688 ( 1988. ). [PubMed] [Google Scholar]
  • 23. ) Hiller , S. A. , Zhuk , R. A. and Lidak , M. J.Analogs of pyrimidine nucleosides. I. N‐(α‐furanidyl) derivatives of natural pyrimidine based and their antimetabolites . Dokl. Akad. Kauk. SSSR , 176 , 332 – 335 ( 1967. ) [ Chem Abstr., 69, 29664j (1968) ]. [PubMed] [Google Scholar]
  • 24. ) Toide , H. , Akiyoshi , H. , Minato , Y. , Okuda , H. and Fujii , S.Comparative studies on the metabolism of 2‐(tetrahydrofuryl)‐5‐fluorouracil and 5‐fluorouracil . Gann , 68 , 553 – 560 ( 1977. ). [PubMed] [Google Scholar]
  • 25. ) Fujii , S. , Ikenaka , K. , Fukushima , M. and Shirasaka , T.Effect of uracil and its derivatives on antitumor activity of 5‐fluorouracil and 1‐(2‐tetrahydrofuryl)‐5‐fluorouracil . Gann , 69 , 763 – 772 ( 1978. ). [PubMed] [Google Scholar]
  • 26. ) Fujii , S. , Kitano , S. , Ikenaka , K. and Shirasaka , T.Effect of coadministration of uracil or cytosine on the antitumor activity of clinical doses of 1‐ (2‐tetrahydrofuryl)‐5 ‐fluorouracil and level of 5‐fluorouracil in rodents . Gann , 70 , 209 – 214 ( 1979. ). [PubMed] [Google Scholar]
  • 27. ) Desgranges , C. , Razaka , G. , Clercq , E. D. , Herdecuijn , P. , Balzarini , J. , Drovillet , F. and Bricaud , H.Effect of (E)‐5‐(2‐bromovinly) uracil on the catabolism and antitumor activity of 5‐fluorouracil in rats and leukemic mice . Cancer Res. , 46 , 1094 – 1101 ( 1986. ). [PubMed] [Google Scholar]
  • 28. ) Tatsumi , K. , Fukushima , M. , Shirasaka , T. and Fujii , S.Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5‐fluorouracil degradation in rat liver extracts . Jpn. J. Cancer Res. , 78 , 748 – 755 ( 1987. ). [PubMed] [Google Scholar]
  • 29. ) Kurono , M. , Chiba , T. and Fujii , S.5‐Fluorouracil derivatives . Jpn. Patent No. 50‐37787 , 753 – 758 ( 1975. ) [ Chem. Abstr., 84, 17405t (1975) ].
  • 30. ) Fujii , S.5‐Fluorouracil derivatives . Jpn. Patent No. 63‐20127 , 195 – 203 ( 1988. ).
  • 31. ) Au , J. L‐S. and Sadee , W.Activation of ftorafur (R, S‐1‐(tetrahydro‐2‐furanyl)‐5‐fluorouracil) to 5‐fluorouracil and γ‐butyrolactone . Cancer Res. , 40 , 2814 – 2819 ( 1980. ). [PubMed] [Google Scholar]
  • 32. ) Fujii , S. , Kitano , S. , Ikenaka , K. , Fukushima , M. , Nakamura , H. , Maehara , Y. and Shirasaka , T.Effect of coadministration of thymine or thymidine on the antitumor activity of l‐(2‐tetrahydrofuryl)‐5‐fluorouracil and 5‐fluorouracil . Gann , 71 , 100 – 106 ( 1980. ). [PubMed] [Google Scholar]

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