Abstract
The antitumor activity of 5′‐deoxy‐5‐fluorouridine (DFUR), a prodrug of 5‐fluorouracil (5‐FU), is markedly enhanced if DFUR treatment is combined with (E)‐5‐(2‐bromovinyl)‐2′‐deoxyuridine (BVDU). Combined oral administration of DFUR (10 mg/kg) and BVDU (10 mg/kg) three times (every 3 h) per day for 5 days afforded greater antitumor activity than a single dose of DFUR (300 mg/kg/day) for 5 days in mice bearing either adenocarcinoma 755 or Lewis lung carcinoma, while in the colon 26 system the antitumor effects of both treatment regimens were equivalent. Thus, a low‐dose regimen of DFUR when combined with BVDU provides a similar or greater antitumor activity than a high‐dose regimen of DFUR that is not combined with BVDU. The area under the curve of plasma 5‐FU following a treatment with the combination of DFUR (10 mg/kg) and BVDU (10 mg/kg) was equal to that following DFUR (300 mg/kg) treatment.
Keywords: 5′‐Deoxy‐5‐fluorouridine, (E)‐5‐(2‐Bromovinyl)‐2′‐deoxyuridine, Antitumor activity, Combination therapy
Full Text
The Full Text of this article is available as a PDF (281.9 KB).
REFERENCES
- 1. ) Iigo , M. , Araki , E. , Nakajima , Y. , Hoshi , A. and De Clercq , E.Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5‐fluorouracil against adenocar‐cinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5‐fluorouracil levels . Biochem. Pharmacol. , 37 , 1609 – 1613 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Armstrong , R. D. and Diasio , R. B.Selective activation of 5′‐deoxy‐5‐fluorouridine by tumor cells as basis for an improved therapeutic index . Cancer Res. , 41 , 4891 – 4894 ( 1981. ). [PubMed] [Google Scholar]
- 3. ) Au , J. L‐S. , Rustum , Y. M. , Minowada , J. and Srivastave , B. I. S.Differential selectivity of 5‐fluorouracil and 5′‐deoxy‐5‐fluorouridine in cultured human B lymphocytes and mouse L1210 leukemia . Biochem. Pharmacol. , 32 , 541 – 546 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Ishitsuka , H. , Miwa , M. , Takemoto , K. , Fukuoka , K. , Itoga , A. and Maruyama , H. B.Role of uridine phosphorylase for antitumor activity of 5′‐deoxy‐5‐fluorouridine . Gann , 71 , 112 – 123 ( 1980. ). [PubMed] [Google Scholar]
- 5. ) Iigo , M. , Nishikata , K. , Nakajima , Y. , Hoshi , A. , Okudaira , N. , Odagiri , H. and De Clercq , E.Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5′‐deoxy‐5‐fluorouridine against adenocarcinoma 755 in mice: correlation with pharmacokinetics of plasma 5‐fluorouracil levels . Biochem. Pharmacol. , 38 , 1885 – 1889 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Chaudhuri , N. K. , Mukherjee , K. L. and Heidelberger , C.Studies on fluorinated pyrimidines. VII. The degradative pathway . Biochem. Pharmacol. , 1 , 328 – 341 ( 1958. ). [Google Scholar]
- 7. ) Desgranges , C. , Razaka , G. , de Clercq , E. , Herdewijn , P. , Balzarini , J. , Drouillet , F. and Bricaud , H.Effect of (E)‐5‐(2‐bromovinyl)uracil on the catabolism and antitumor activity of 5‐fluorouracil in rats and leukemic mice . Cancer Res. , 46 , 1094 – 1101 ( 1986. ). [PubMed] [Google Scholar]
- 8. ) Jones , A. S. , Verhelst , G. and Walker , R. T.The synthesis of the potent antiherpes virus agent, (E)‐5‐(2‐bromovinyl)‐2′‐deoxyuridine and related compounds . Tetrahedron Lett. , 4415 – 4418 ( 1979. ).
- 9. ) Miwa , M. , Nakamura , J. and Ishitsuka , H.A simple and convenient assay method for phosphorolysis of 5′‐deoxy‐5‐fluorouridine . Gann , 72 , 965 – 968 ( 1981. ). [PubMed] [Google Scholar]
- 10. ) Kopper , L. , Hanh , T. V. and Lapis , K.Experimental model for liver metastasis formation using Lewis lung tumor . J. Cancer Res. Clin. Oncol. , 103 , 31 – 38 ( 1982. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. ) Uehara , N. , Baba , H. , Nitta , K. , Kunimoto , T. , Takeuchi , M. , Sasaki , T. and Tanaka , T.The therapeutic effects of orally administered 5′‐deoxy‐5‐fluorouridine, 1‐(2‐tetra‐hydrofuryl)‐5‐fluorouracil and 5‐fluorouracil on experimental murine tumor . Jpn. J. Cancer Res. , 76 , 1034 – 1041 ( 1985. ). [PubMed] [Google Scholar]
- 12. ) Desgranges , C. , Razaka , G. , Bricaud , H. and De Clercq , E.Inhibition of the degradation of thymine and 5‐substituted uracil analogues by (E)‐5‐(2‐bromovinyl)uracil in vivo . Biochem. Pharmacol. , 34 , 403 – 404 ( 1985. ). [Google Scholar]