Summary
The antitumor activity of the fluorinated pyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), and 5-fluoro-2′-deoxyuridine (FdUrd) against P388 leukemia was markedly potentiated by the addition of guanosine (Guo), resulting in therapeutic synergism. Any combination of FUra at 1–20 mg/kg, FUrd at 0.3–1 mg/k, or FdUrd at 1–100 mg/kg with Guo at 100 mg/kg significantly potentiated the activity of FUra, FUrd, or FdUrd, respectively. The potentiation of these fluorinated pyrimidines by guanosine was abolished by the simultaneous administration of cytidine or uridine, but not of thymidine. In particular, cytidine was the strongest inhibitor of antitumor activity of these fluorinated pyrimidines, alone and in combination with guanosine.
To obtain more effective treatment with the combination of various fluorinated pyrimidines and Guo, the influence of the molar ratios of Guo to the fluorinated pyrimidines on the antitumor activity against P388 leukemia was investigated. The increase in life-span became more pronounced with increasing molar ratios. The optimal molar ratios of Guo/FUra, Guo/FUrd, and Guo/FdUrd were more than 5, 100, and 5, respectively.
Similar content being viewed by others
References
Ardalan B, Buscaglia MD, Schein PS (1978) Tumor 5-fluorodeoxyuridylate concentration as a determinant of 5-fluorouracil response. Biochem Pharmacol 27:2009–2013
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
Birnie GD, Kroeger H, Heidelberger C (1963) Studies of fluorinated pyrimidines. XVIII. The degradation of 5-fluoro-2′-deoxyuridine and related compounds by nucleoside phosphorylase. Biochemistry 2:566–572
Bloch A (1974) Metabolic conditioning and metabolic actuation: Experimental approaches to cancer chemotherapy involving combinations of metabolites and antimetabolites. Cancer Chemother Rep 58:471–477
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
Fujii S, Ikenaka K, Fukushima M, Shirasaka T (1978) Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann 69:763–772
Fujii S, Kitano S, Ikenaka K, Fukushima M, Nakamura H, Maehara Y, Shirasaka T (1980) Effect of coadministration of thymine or thymidine on the antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil and 5-fluorouracil. Gann 71:100–106
Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer RJ, Pleven E, Scheiner J (1957) Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature 179:663–666
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, Ando N, Hoshi 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, Kuretani K, Hoshi A (1983a) 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 (1983b) Potentiation of the chemotherapeutic effect of 5-fluorouracil by combination with guanosine 5′ monophosphate. Gann 74:291–298
Ikenaka K, Shirasaka T, Kitano S, Fujii S (1979) Effect of uracil on metabolism of 5-fluorouracil in vitro. Gann 70:353–359
Jato J, Windheuser JJ (1973) 5-Fluorouracil and derivatives in cancer chemotherapy. III. In vivo enhancement of antitumor activity of 5-fluorouracil (FU) and 5-fluoro-2′-deoxyuridine (FUDR). J Pharm Sci 62:1975–1978
Kanzawa F, Hoshi A, Kuretani K (1979) Improvement of therapeutic effect of 5-fluorouracil by orotic acid. J Pharmacobiodyn 2:257–259
Kanzawa F, Hoshi A, Kuretani K (1981) Influence of duration of exposure to 5-fluorouracil on antiproliferating activity against cultured murine lymphoma cells. Br J Cancer 44:757–759
Kessel D, Hall TC (1969) Influence of ribose donors on the action of 5-fluorouracil. Cancer Res 29:1749–1754
Kessel D, Hall TC, Wodinsky I (1966) Nucleotide formation as a determinant of 5-fluorouracil response in mouse leukemia. Science 154:911–913
Klubes P, Conelly K, Ingeborg C, Mandel HG (1978) Effects of 5-fluorouracil on 5-fluorodeoxyuridine 5′-monophosphate and 2-deoxyuridine 5′-monophosphate pools, and DNA snythesis in solid mouse L1210 and rat Walker 256 tumors. Cancer Res 38:2325–2331
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 RM, 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, Shirasaka T, Fujii S (1982) Activities of various enzymes of pyrimidine nucleotide and DNA syntheses in normal and neoplastic human tissues. Gann 73:289–298
Mandel HG (1969) The incorporation of 5-fluorouracil into RNA and its molecular consequences. Prog Mol Subcell Biol 1:82–135
Osswald H, Youssef M (1979) Potentiation of the chemotherapeutic action of 5-fluorouracil by combination with cytidine or guanosine on HRS-sarcoma. J Cancer Res Clin Oncol 93:241–244
Reichard P, Sköld O, Klein G (1959) Possible enzymatic mechanism for the development of resistance against fluorouracil in ascites tumors. Nature 183:939–941
Reyes P, Hall TC (1969) Synthesis of 5-fluorouridine 5′ phosphate by a pyrimidine phosphoribosyltransferase of mammalian origin. II. Correlation between the tumor levels of the enzyme and the 5-fluorouracil-promoted increase in survival of tumor-bearing mice. Biochem Pharmacol 18:2587–2590
Santelli G, Valeriote F (1978) In vivo enhancement of 5-fluorouracil cytotoxicity to AKR leukemia cells by thymidine in mice. J Natl Cancer Inst 61:843–847
Santi DV, McHenry CS, Sommer H (1974) Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13:471–481
Yoshida M, Hoshi A, Kuretani K (1980) The difference in mechanism of action of 5-fluorouracil and its nucleosides in L5178Y cells. J Pharmacobiodyn 3:374–379
Zieve GW (1981) Two groups of small stable RNAs. Cell 25:296–297
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Iigo, M., Hoshi, A. Effect of guanosine on antitumor activity of fluorinated pyrimidines against P 388 leukemia. Cancer Chemother. Pharmacol. 13, 86–90 (1984). https://doi.org/10.1007/BF00257120
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00257120