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Effect of guanosine on antitumor activity of fluorinated pyrimidines against P 388 leukemia

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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.

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  1. 1.

    Ardalan B, Buscaglia MD, Schein PS (1978) Tumor 5-fluorodeoxyuridylate concentration as a determinant of 5-fluorouracil response. Biochem Pharmacol 27:2009–2013

  2. 2.

    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

  3. 3.

    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

  4. 4.

    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

  5. 5.

    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

  6. 6.

    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

  7. 7.

    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

  8. 8.

    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

  9. 9.

    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

  10. 10.

    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

  11. 11.

    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

  12. 12.

    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

  13. 13.

    Ikenaka K, Shirasaka T, Kitano S, Fujii S (1979) Effect of uracil on metabolism of 5-fluorouracil in vitro. Gann 70:353–359

  14. 14.

    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

  15. 15.

    Kanzawa F, Hoshi A, Kuretani K (1979) Improvement of therapeutic effect of 5-fluorouracil by orotic acid. J Pharmacobiodyn 2:257–259

  16. 16.

    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

  17. 17.

    Kessel D, Hall TC (1969) Influence of ribose donors on the action of 5-fluorouracil. Cancer Res 29:1749–1754

  18. 18.

    Kessel D, Hall TC, Wodinsky I (1966) Nucleotide formation as a determinant of 5-fluorouracil response in mouse leukemia. Science 154:911–913

  19. 19.

    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

  20. 20.

    Kufe DW, Major PP (1981) 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. J Biol Chem 256:9802–9805

  21. 21.

    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

  22. 22.

    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

  23. 23.

    Mandel HG (1969) The incorporation of 5-fluorouracil into RNA and its molecular consequences. Prog Mol Subcell Biol 1:82–135

  24. 24.

    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

  25. 25.

    Reichard P, Sköld O, Klein G (1959) Possible enzymatic mechanism for the development of resistance against fluorouracil in ascites tumors. Nature 183:939–941

  26. 26.

    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

  27. 27.

    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

  28. 28.

    Santi DV, McHenry CS, Sommer H (1974) Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13:471–481

  29. 29.

    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

  30. 30.

    Zieve GW (1981) Two groups of small stable RNAs. Cell 25:296–297

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Correspondence to Masaaki Iigo.

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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

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  • Leukemia
  • Cancer Research
  • Effective Treatment
  • Pyrimidine
  • Thymidine