Summary
Ribavirin (300 and 250 mg/kg i.p., respectively) had a toxic effect on hemopoietic stem cells in normal mice; CFU-S, CFU-C, and especially CFU-E were reduced after a single treatment. The drug was further studied in mice infected with the polycythemia-inducing strain of the Friend virus (FV-P). In these mice a specific erythropoietin-independent CFU-E population (CFU-EI) replaces the normal erythropoiesis and can be considered a tumor cell population. With the in vitro technique for CFU-E, CFU-EI can easily be quantified and used as a sensitive marker for the development of the disease. Repeated doses of ribavirin reduced the increase of spleen weight after FV-P infection and the progressive transformation of normal CFU-E into CFU-EI was delayed. The further development of the disease remained unaltered. In vitro, CFU-E and CFU-EI were inhibited at the same concentrations when the drug was added to the culture medium. In mice pretreated with multiple doses of hydroxyurea, ribavirin delayed the recurrence of Friend leukemia as seen from the spleen weight increase, but the CFU-E population was predominantly Ep-independent. It is concluded that the effects of the drug were due to its cytotoxicity rather than to a specific antiviral effect.
Similar content being viewed by others
References
Ayrosa-Galvao PA, Castro IO (1977) The effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide on acute viral hepatitis. Ann N Y Acad Sci 284:272
Dowling JN, Postic B, Guerarra LD (1976) Effect of ribavirin on murine cytomegalovirus infection. Antimicrob. Agents Chemother 10:809
Horoszewicz JS, Leong SS, Carter WA (1975) Friend leukemia: rapid development of erythropoietin-independent hematopoietic precursors. J Natl Cancer Inst 54:265
Huffman JR, Sidwell RW, Khare GP, Witkowski JT, Allen LB, Robins RK (1973) In vitro effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole ICN 1229) on deoxyribonucleic acid and ribonucleic viruses. Antimicrob Agents Chemother 3:235
Iscove NN, Sieber F, Winterhalter KH (1974) Erythroid colony formation in cultures of mouse and human bone marrow: Analysis of the requirement for erythropoietin by gel filtration and affinity chromatography on agarose concanavalin A. J Cell Physiol 83:309
Katz E, Magalith E, Winer B (1976) Inhibition of vaccinia virus growth by the nucleoside analogue 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole, Ribavirin). J Gen Virol 32:327
Khare GP, Sidwell RW, Witkowski JT, Simon LN, Robins RK (1973) Suppressionby 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole ICN 1229) of influenza virus-induced infections in mice. Antimicrob Agents Chemother 3:517
Liao SK, Axelrad AA (1975) Erythropoietin-independent erythroid colony formation in vitro by hematopoietic cells of mice infected with Friend virus. Int J Cancer 15:467
Öberg B, Helgstrand E (1977) Selective inhibition of viral polymerases by ribavirin triphosphate. Curr Chemother 1:332
Opitz U, Seidel HJ, Bertoncello I (1978) Erythroid stem cells in Friend virus infected mice. J Cell Physiol 96:95
Oxford JS (1975) Inhibition of the replication of Influenza A and B viruses by a nucleoside analogue (Ribavirin). J Gen Virol 28:409
Prusiner P, Sundaralingam M (1973) A new class of synthetic nucleoside analogues with broad-spectrum antiviral properties. Natl New Biol 224:116
Salido-Rengell F, Nasser-Quirones H, Briseno-Garcia B (1977) Clinical evaluation of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin) in a double blind study during the outbreak of influenza. Ann NY Acad Sci 284:272
Scholtissek C (1976) Inhibition of influenza RNA synthesis by Virazole (Ribavirin). Arch Virol 50:349
Seidel HJ, Opitz U (1979) Hematopoietic stem cells in Friend virus infected mice undergoing chemotherapy: Remission and relapse of erythropoietin-independent erythropoiesis induced by hydroxyurea. J Natl Cancer Inst 62:531
Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK (1972) Broad-spectrum antiviral activity of Virazole: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science 177:705
Sidwell RW, Allen LB, Khare GP, Huffman JH, Witkowski JT, Simon LN, Robins RK (1973) Effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole ICN 1229) on herpes and vaccinia keratitis and encephalitis in laboratory animals. Antimicrob Agents Chemother 3:242
Sidwell RW, Allen LB, Huffman JH, Witkowski JT, Simon L (1975) Effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin) on Friend Leukemia virus infections in mice. Proc Soc Exp Biol Med 148:854
Stephenson JR, Axelrad AA, McLeod DL, Shreeve MM (1971) Induction of colonies of hemoglobin-synthesizing cells by erythropoietin in vitro. Proc Natl Acad Sci USA 68:1542
Streeter DG, Khare GP, Sidwell RW, Simon LN (1972) Virazole: Biochemical studies on the mechanism of inhibition of herpes virus replication. Fed Proc 31:576
Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK, Simon LN (1973) Mechanism of action of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad spectrum antiviral agent. Proc Natl Acad Sci USA 70:1174
Suganuma I, Ishida N (1973) An evaluation of a new antiviral agent “Virazole” against influenza virus infections. Tohoku J Exp Med 10:405
Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213
Witkowski JT, Robins RK, Sidwell RW, Simon LN (1972) Design, synthesis, and broad antiviral activity of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem 15:1150
Zertuche HF, Parches RD (1977) Clinical experiences using the antiviral 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin) in Mexico. Ann N Y Acad Sci 284:284
Author information
Authors and Affiliations
Additional information
Supported by the Deutsche Forschungsgemeinschaft
Rights and permissions
About this article
Cite this article
Opitz, U., Seidel, H.J. & Streissle, G. Effects of ribavirin on the development of the Friend leukemia. J Cancer Res Clin Oncol 98, 41–50 (1980). https://doi.org/10.1007/BF00413175
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00413175