Summary
The effect of inosine, guanosine, and guanosine 5′-monophosphate (GMP) on the antitumor activity of 5′-deoxy-5-fluorouridine (5′-DFUR) was investigated using P388 leukemia and P815 mastocytoma.
The antitumor activity of 5′-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5′-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5′-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILSmax/dose at ILS30) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5′-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5′-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system.
The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Arakawa M, Shimizu F, Sasagawa K, Inomata T, Shinkai K (1981) Antitumor activity of methyl (5-fluoro-1H-2-oxo-4-pyrimidinyl-β-D-glucopyranosid) uronate against various experimental tumours. Gann 72:220–225
Ardalan B, Cooney DA, Jayaram HN, Carrico CK, Glazer RI, MacDonald J, Schein PS (1980) Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil. Cancer Res 40:1431–1437
Armstrong RD, Diasio RB (1980) Metabolism and biological activity of 5′-deoxy-5-fluorouridine, a novel fluoropyrimidine. Cancer Res 40:3333–3338
Armstrong RD, Diasio RB (1981) Selective activation of 5′-deoxy-5-fluorouridine by tumor cells as a basis for an improved therapeutic index. Cancer Res 41:4891–4894
Au J L-S, Rustum YM, Minowada J, Srivastava BIS (1983) Differential selectivity of 5-fluorouracil and 5′-deoxy-5-fluorouridine in cultured human B lymphocytes and mouse L1210 leukemia. Biochem Pharmacol 32:541–546
Bollag W, Hartmann HR (1980) Tumor inhibitory effects of a new fluorouracil derivative: 5′-deoxy-5-fluorouridine. Eur J Cancer 16:427–432
Cook AF, Holman MJ, Kramer MJ, Trown PW (1979) Fluorinated pryimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5′-deoxy-5-fluoropyrimidine nucleosides. J Med Chem 22:1330–1335
Cory JG, Crumley J, Wilkinson DS (1977) Evidence for role of purine nucleoside phosphorylase in sensitivity of Novikoff hepatoma cells to 5-fluorouracil. Adv Enzyme Regul 15:153–166
Hiller AS, Zhuk RA, Lidak MY (1968) Works of the first All Union Conference on Malignant Tumors. Riga, USSR, pp 1111–1112
Iigo M, Ando N, Noshi A, Kuretani K (1982) Effect of pyrimidines, purines and their nucleosides on antitumor activity of 5-fluorouracil against L1210 leukemia. J Pharmacobiodyn 5:515–520
Iigo M, Hoshi A (1984) Effect of guanosine on antitumor activity of fluorinated pyrimidines against P388 leukemia. Cancer Chemother Pharmacol 13:86–90
Iigo M, Hoshi A (1984) Influence of molar ratio on the combination effect of 5-fluorouracil with guanosine 5′-monophosphate on P388 and L1210 leukemias. Eur J Cancer Clin Oncol 20:411–415
Iigo M, Hoshi A, Nakamura A, Kuretani K (1979) Antineoplastic effect of orally administered l-alkylcarbamoyl derivatives of 5-fluorouracil on sc implanted Lewis lung carcinoma and B 16 melanoma. Cancer Treat Rep 63:1895–1899
Iigo M, Kuretani K, Hoshi A (1983) Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites sarcoma 180 tumor system. Cancer Res 43:5687–5694
Iigo M, Nakajima Y, Kuretani K, Hoshi A (1983) Potentiation of the chemotherapeutic effect of 5-fluorouracil by combination with guanosine 5′-monophosphate. Gann 74:291–298
Ishitsuka H, Miwa M, Takemoto K, Fukuoka K, Itoga A, Maruyama HB (1980) Role of uridine phosphorylase for antitumor activity of 5′-deoxy-5-fluorouridine. Gann 71:112–123
Kessel D, Hall TC (1969) Influence of ribose donors on the action of 5-fluorouracil. Cancer Res 29:1749–1954
Kessel D, Hall TC, Wodinsky I (1966) Nucleotide formation as a determinant of 5-fluorouracil response in mouse leukemia. Science 154:911–913
Kufe DW, Major PP (1981) 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. J Biol Chem 256:9802–9805
Laskin JD, Evans KM, Slocum HK, Burke D, Hakala MT (1979) Basis for natural variation in sensitivity to 5-fluorouracil in mouse and human cells in culture. Cancer Res 39:383–390
Maehara Y, Nakamura H, Nakane Y, Kawai K, Okamoto M, Nagayama S (1982) Activities of various enzymes of pyrimidine nucleotide and DNA syntheses in normal and neoplastic human tissues. Gann 73:289–298
Myers CE, Diasio RB, Eliot HM, Chabner BA (1976) Pharmacokinetics of the fluoropyrimidines: implications for their clinical use. Cancer Treat Rev 3:175–183
Ohta Y, Sueki K, Nitta K, Takemoto K, Ishitsuka H, Yagi Y (1980) Comparative studies on the immunosuppressive effect among 5′-deoxy-5-fluorouridine, ftorafur, and 5-fluorouracil. Gann 71:190–196
Rustum YM, Danhauser L, Luccioni C, Au JL (1981) Determinants of response to antimetabolites and their modulation by normal purine and pyrimidine metabolites. Cancer Treat Rep 65:73–82
Suzuki S, Hongu, Y, Fukazawa H, Ichihara S, Shimizu H (1980) Tissue distribution of 5′-deoxy-5-fluorouridine and derived 5-fluorouracil in tumor-bearing mice and rats. Gann 71:238–245
Tezuka M, Tamemasa O (1983) Potentiation of the antitumor effect of 5-fluorouracil by some nucleotides, and their possible role in the potentiation. Jpn J Exp Med 53:155–163
Uehara N, Baba H, Nitta K, Kunimoto T, Takeuchi M, Sasaki T, Tanaka T (1985) 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 (Gann) 76:1034–1041
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Iigo, M., Miwa, M., Ishitsuka, H. et al. Potentiation of the chemotherapeutic action of 5′-deoxy-5-fluorouridine in combination with guanosine and related compounds. Cancer Chemother. Pharmacol. 19, 61–64 (1987). https://doi.org/10.1007/BF00296258
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00296258