Abstract
N4‐Trimethoxybenzoyl‐5′‐deoxy‐5‐fluorocytidine (Ro 09–1390), a prodrug of the cytostatic 5′‐deoxy‐5‐fluorouridine (5′‐DFUR), was synthesized with the aim of reducing of the dose‐limiting toxicity of 5′‐DFUR, which is diarrhea. In mice bearing Lewis lung carcinoma, 5′‐DFUR given po produced a substantial amount of 5‐fluorouracil (5‐FU) in the intestinal tract as well as in tumors, where the enzyme pyrimidine nucleoside phosphorylase, essential for conversion of 5′‐DFUR to 5‐FU, is predominantly located. With the oral administration of Ro 09–1390 only a small amount of 5‐FU was formed in the intestine; however, the administration of Ro 09–1390 and 5′‐DFUR at the same dose produced similar amounts of 5‐FU in tumor tissues. These differences in metabolism were reflected in their toxicity and antitumor efficacy. The administration of 5′‐DFUR resulted in damage to the intestinal mucosal membrane and diarrhea in normal mice, whereas Ro 09–1390 was much less toxic to the intestinal tract. As regards antitumor activity, Ro 09–1390 and 5′‐DFUR at equivalent doses inhibited the growth of Lewis lung carcinoma to similar extents. Since Ro 09–1390 was much less toxic to the intestinal tract than 5′‐DFUR, mice bearing Lewis lung carcinoma could be given Ro 09–1390 daily over a longer period and at a higher dose, resulting in a longer survival time.
Keywords: Antitumor activity, Intestinal toxicity, Trimethoxybenzoyl‐5′‐deoxy‐5‐fluro‐cytidine (Ro 09–1390), 5′‐Deoxyfluorocytidine, 5′‐Deoxy‐5‐fluorouridine
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REFERENCES
- 1. ) Taguchi , T. , Sakai , K. , Terasawa , H. , Irie , K. , Okajima , K. , Yamamoto , M. , Kawahara , T. , Satomi , T. , Tomita , K. , Yamaguchi , A. , Shiratori , T. , Ito , A. , Enomoto , I. , Kimura , M. , Satani , M. , Shimoyama , T. , Okamoto , E. , Okuno , G. , Kurabori , T. and Okamura , T.Phase II study of 5′‐DFUR (5′‐deoxy‐5‐fluorouridine) by cooperative study group . Jpn. J. Cancer Chemother. , 12 , 2179 – 2184 ( 1985. ) ( in Japanese ). [PubMed] [Google Scholar]
- 2. ) Niitani , H. , Kimura , K. , Saito , T. , Nakao , I. , Abe , O. , Urushizaki , I. , Ohta , K. , Yoshida , Y. , Kimura , T. , Kurihara , M. , Takeda , C. , Taguchi , T. , Terasawa , T. , Tominaga , K. , Furue , H. , Wakui , A. and Ogawa , N.Phase II studies of 5′‐deoxy‐5‐fluorouridine (5′‐DFUR) on patients with malignant cancer. Multi‐institutional cooperative study . Jpn. J. Cancer Chemother. , 12 , 2044 – 2051 ( 1985. ) ( in Japanese ). [PubMed] [Google Scholar]
- 3. ) Taguchi , T. , Terasawa , T. , Abe , O. , Yoshida , Y. , Tominaga , T. and Ogawa , N.A comparative study between 5′‐DFUR and Tegafur in recurrent breast cancer . Jpn. J. Cancer Chemother. , 12 , 2052 – 2060 ( 1985. ) ( in Japanese ). [PubMed] [Google Scholar]
- 4. ) Tominaga , T. , Kitamura , M. , Hayashi , K. , Takahashi , I. and Kosaki , G.Phase II study of 5′‐DFUR for gastrointestinal and breast cancer . Jpn. J. Cancer Chemother. , 12 , 2172 – 2178 ( 1985. ) ( in Japanese ). [PubMed] [Google Scholar]
- 5. ) 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‐fluoro‐uridine . Gann , 71 , 112 – 123 ( 1980. ). [PubMed] [Google Scholar]
- 6. ) Miwa , M. , Nishimura , J. , Kamiyama , T. and Ishitsuka , H.Conversion of 5′‐deoxy‐5‐fluorouridine to 5‐FU by pyrimidine nucleoside phosphorylase in normal and tumor tissues from rodents bearing tumors and cancer patients . Jpn. J. Cancer Chemother. , 14 , 2924 – 2929 ( 1987. ) ( in Japanese ). [PubMed] [Google Scholar]
- 7. ) Suzuki , S. , Hongu , Y. , Fukazawa , H. , Ichihara , S. and Shimizu , H.Tissue distribution of 5′‐deoxy‐5‐fluorouridine and derived 5‐fluorouracil in tumor‐bearing mice and rats . Gann , 71 , 238 – 245 ( 1980. ). [PubMed] [Google Scholar]
- 8. ) Kreis , W. , Watanabe , K. A. and Fox , J. J.Structural requirement for the enzymatic deamination of cytosine nucleosides . Helv. Chim. Acta , 61 , 1011 – 1016 ( 1978. ). [Google Scholar]
- 9. ) Camiener , G. W. and Smith , C.Studies of the enzymatic deamination of cytosine arabinoside. I. Enzyme distribution and species specificity . Biochem. Pharmacol. , 14 , 1405 – 1416 ( 1965. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Umeda , I. , Fujiu , M. , Yokose , K. , Miwa , M. and Ishitsuka , H.European Patent No. 87.116926.4 ( 1989. ).
- 11. ) 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]
- 12. ) Ninomiya , Y. , Ryu , M. , Matsuura , N. , Fujimoto , K. , Miwa , M. and Ishitsuka , H.Antitumor activity and the toxicity on the immune system and the intestine of fluorinated pyrimidines, FUra, 5′‐DFUR, tegafur and UFT . Jpn. J. Cancer Chemother. , 15 , 1747 – 1754 ( 1988. ). [PubMed] [Google Scholar]
- 13. ) 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‐tetrahydrofuryl)‐5‐fluorouracil and 5‐fluorouracil on experimental murine tumors . Jpn. J. Cancer Res. , 76 , 1034 – 1041 ( 1985. ). [PubMed] [Google Scholar]
- 14. ) Bollag , W. and Hartmann , H. R.Tumor inhibitory effects of a new fluorouracil derivatives: 5′‐deoxy‐5‐fluorouridine . Eur. J. Cancer , 16 , 427 – 432 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Kono , H. , Hara , Y. , Sugata , S. , Karube , Y. , Matsushima , Y. and Ishitsuka , H.Activation of 5′‐deoxy‐5‐fluorouridine by thymidine phosphorylase in human tumors . Chem. Pharm. Bull. , 31 , 175 – 178 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Miwa , M. , Cook , A. and Ishitsuka , H.Enzymatic cleavage of various fluorinated pyrimidine nucleosides to 5‐fluorouracil and their antiproliferative activities in human and murine tumor cells . Chem. Pharm, Bull. , 34 , 4225 – 4232 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Fujita , H. , Ogawa , K. , Nakagawa , H. , Kawaguchi , K. , Nakagawa , Y. and Doi , Y.Pharmacokinetics of 5′‐deoxy‐5‐fluorouridine (5′‐DFUR) by oral administration . J. Jpn. Soc. Cancer Ther. , 18 , 916 – 926 ( 1983. ). [PubMed] [Google Scholar]
- 18. ) Alberto , M. , Rozencweig , M. , Clavel , M. , Siegenthaler , P. , Cavelli , F. , Gunedrsen , S. , Runtsch , U. , Renard , J. and Pinedo , H.Phase II study of 5′‐deoxy‐5‐fluorouridine (doxifluridine) in advanced malignant melanoma . Cancer Chemother. Pharmacol. , 16 , 78 – 79 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Alberto , P. , Mermillod , B. , Germano , G. , Kaplan , S. , Weber , W. , Joss , R. , Spati , B. , Martz , G. and Cavalli , F.A randomized comparison of doxifluridine and fluorouracil in colorectal carcinoma . Eur. J. Cancer Clin. Oncol. , 24 , 559 – 563 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Fujita , H. , Ogawa , K. and Kimura , K.In vivo distribution and activation of N4‐behenoyl‐l‐d‐arabinofuranosylcytosine (BH‐AC) . Chemotherapy , 31 , 723 – 732 ( 1983. ) ( in Japanese ). [Google Scholar]
- 21. ) Tsuruo , T. , Hori , K. , Iida , H. , Tsukagoshi , S. and Sakurai , Y.Enzyme catalyzation of the deacylation of N4‐acyl derivatives of 1‐β‐d‐arabinofuranosylcytosine in the mouse liver microsome . Cancer Res. , 42 , 2250 – 2254 ( 1982. ). [PubMed] [Google Scholar]
- 22. ) Mellett , L. B. and Mulliban , L. T.Comparative metabolism of cytosine arabinoside and inhibition of deamination by tetrahydrouridine . Pharmacologist , 10 , 167 ( 1968. ). [Google Scholar]
- 23. ) Ho , D. H. W.Distribution of kinase and deaminase of 1‐β‐d‐arabinofuranosylcytosine in tissues of man and mouse . Cancer Res. , 33 , 2816 – 2820 ( 1973. ). [PubMed] [Google Scholar]