Abstract
Uridine and/or thymidine were administered concomitantly with 5-fluorouracil (5-FU) and 5′-deoxy-5-fluorouridine (5′-dFUR) to mice and rats in order to establish whether the physiological nucleosides actingin vitro as antagonists can diminish fluoropyrimidine toxicityin vivo. In addition, the influence of orally co-administered uridine on antitumor activity of 5-FU and 5′-dFUR in mice has been studied. All co-administrations aggravated the general toxicity of both fluoropyrimidines. Tumor inhibition was enhanced by uridine, but the therapeutic ratio was not improved compared to monotherapy with either 5-FU or 5′-dFUR.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Santelli G, Valeriote F:In vivo enhancement of 5-fluorouracil cytotoxicity to AKR leukemia cells by thymidine in mice.J Natl Cancer Inst 61, 843 (1978).
Spiegelman S, Sawyer R, Nayak R, Stolfi R, Martin D: Improving the anti-tumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation.Proc Natl Acad Sci USA 77, 4966 (1980).
Young C W, Woodcock T M, Martin D S: Modulation of 5-FU action by thymidine in murine and human tumors.Cancer Treatment Rep 65, Suppl 3, 83 (1981).
Klubes P, Cerna I, Meldon M A: Uridine rescue from the lethal toxicity of 5-FU in mice.Cancer Chemother Pharmac 8, 17 (1982).
Martin D S, Stolfi R L, Sawyer R C, Spiegelman S, Young C W: High-dose 5-fluorouracil with delayed uridine ‘rescue’ in mice.Cancer Res 42, 3964 (1982).
Klubes P, Cerna I: Use of uridine rescue to enhance the antitumor selectivity of 5-fluorouracil.Cancer Res 43, 3182 (1983).
Iigo M, Ando N, Hoshi A, Kuretani K: Effect of pyrimidines, purines and their nucleosides on antitumor activity of 5-fluorouracil against L-1210 leukemia.J Pharmac Dyn 5, 515 (1982).
Iigo M, Nakajima Y, Kuretani K, Hoshi A: Potentiation of the chemotherapeutic effect of 5-fluorouracil by combination with guanosine 5-monophosphate.Gann 74, 291 (1983).
Iigo, M, Kuretani K, Hoshi A: Relationship between antitumor effect and metabolites of 5-fluorouracil and guanosine in ascites sarcoma 180 tumor system.Cancer Res 43, 5687 (1983)
Osswald H, Youssef M: Potentiation of the chemotherapeutic action of 5-fluorouracil by combination with cytidine or guanosine on HRS sarcoma.J Cancer Res Clin Onc 93, 241 (1979).
Kirkwood J M, Ensminger W, Rosowsky A, Papathanasopoulos N, Frei E III: Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil with concurrent thymidine infusions in a phase I trial.Cancer Res 40, 107 (1980).
Woodcock T M, Martin D S, Damin L A M, Kemeny N E, Young C W: Combination clinical trials with thymidine and fluorouracil: a phase I and clinical pharmacologic evaluation.Cancer 45, 1135 (1980).
Leyva A, van Groeningen C J, Kraal I, Gall H, Peters G J, Lankelma J, Pinedo H M: Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity.Cancer Res 44, 5928 (1984).
Cook A F, Holman M J, Kramer M J, Trown P W: Fluorinated pyrimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5′-deoxy-5-fluoropyrimidine nucleosides.J Med Chem 22, 1330 (1979).
Bollag W, Hartmann H R: Tumor inhibiting effects of a new fluorouracil derivative: 5′ deoxy-5-fluorouridine.Eur J Cancer 16, 427 (1980).
Hartmann H R, Bollag W: 5′-Desoxy-5-fluorouridin (5-DFUR), ein neuer tumorhemmender Pyrimidin-Antimetabolit.Schweiz Med Wschr 110, 1078 (1980).
Teelmann K: Reduced toxicity of intravenous 5′-deoxy-5fluorouridine (5′-dFUR) in comparison with 5-fluorouracil in rats, in Brown S S, Davies D S (eds):Organ-directed Toxicity, Chemical Indices and Mechanisms (IUPAC). Oxford. Pergamon Press (1981).
Kurihara M, Saito T, Niitani H, Yano T, Taguchi S, Hatta Y, Hasegawa K, Suwa T, Yasui A: Study on efficacy and safety of 5′-deoxy-5-fluorouridine (5′-dFUR) by intermittent administration. Abstract,Proc 14th Int Congr Chemotherapy, Tokyo, Japan (1985).
Taguchi T, Abe O, Terasawa T, Tominaga T, Yoshida Y: Clinical trial of 5′-deoxy-5-fluorouridine (5′-dFUR) for breast cancer. Abstract,Proc 14th Int Congr Chemotherapy, Tokyo, Japan (1985).
Hartmann H R, Matter A: Antiproliferative action of a novel fluorinated uridine analog, 5′-deoxy-5-fluorouridine, measuredin vitro andin vivo on four different murine tumor lines.Cancer Res 42, 2412 (1982).
Hartmann H R, Heintz R C: Tissue distribution of 5′-dFUR and 5-fluorouracil in Lewis lung carcinomabearing mice.Current Chemother Immunother, Proc 12th Int Congr Chemotherapy, Florence, Italy (1981).
Ishitsuka H, Miwa M, Takemoto K, Hoga A, Maruyama H B: Probable role of uridine phosphorylase for antitumor activity of 5′-deoxy-5-fluorouridine.Gann 71, 112 (1980).
Calabresi P, Parks R E Jr: Chemotherapy of neoplastic diseases, in Goodman L S, Gilman A (eds):The Pharmacological Basis of Therapeutics, 6th edn, pp. 1278–1280. New York, Macmillan (1980).
Tuchman M, Rumnaraine M L R, O’Dea R F: Effects of uridine and thymidine on the degradation of 5-fluorouracil, uracil and thymine by rat liver dihydropyrimidine dehydrogenase.Cancer Res 45, 5553 (1985).
Spiegelman S Nayak R, Sawyer R, Stolfi R, Martin D: Potentiation of the anit-tumor activity of 5-FU by thymidine and its correlation with the formation of (5-FU) RNA.Cancer 45, 1129 (1980).
Tuchman M, Stoeckeler J S, Kiang D T, O’Dea R F, Ramnaraine M L, Mirkin B L: Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity.New Engl J Med 313, 245 (1985).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hartmann, H.R., Bollag, W. Modulation of the effects of fluoropyrimidines on toxicity and tumor inhibition in rodents by uridine and thymidine. Med. Oncol. & Tumor Pharmacother. 3, 111–118 (1986). https://doi.org/10.1007/BF02934563
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02934563