Phase and cell cycle specificity of pyrazofurin action

E. Oláh, M. S. Lui, D. Y. Tzeng, G. Weber

Research output: Contribution to journalArticle

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Abstract

Pyrazofurin killed hepatoma 3924A cells in tissue culture with a 50% lethal dose of 0.4 μM, as determined by the colony-forming ability of the cells after 7-days incubation with the drug. Only in the logarithmic phase of growth were the hepatoma cells sensitive to the cytotoxic action of Pyrazofurin which had no detectable effect on plateau-phase cells. In the logarithmic growth phase, treatment of the culture with Pyrazofurin for 1 or 2 hr resulted in a biphasic dose-response curve. In synchronized tumor cell cultures, it was shown that the cells sensitive to Pyrazofurin were those in early G1 and early and mid-S phases of the cycle. Uridine and cytidine protected hepatoma 3924A cells from the cytotoxic action of Pyrazofurin. In the presence of 0.5 μM Pyrazofurin for 7 days, an equimolar concentration of uridine resulted in 70% survival, and 5 to 10 μM uridine provided complete protection. In the presence of 1 μM Pyrazofurin, cytidine (1.0 m(M)) provided 80% protection, and uridine (0.1 m(M)) resulted in 90% survival; hypoxanthine and uracil were ineffective. In hepatoma 3924A cells, uridine and cytidine were rapidly incorporated into trichloroacetic acid soluble material. Uracil was incorporated at a slower rate. Pyrazofurin enhanced the incorporation of uridine into nucleic acids 2-fold and that of uracil 3-fold. In the logarithmically growing hepatoma cells, the activity of orotidine 5'-monophosphate decarboxylase (EC 4.1.1.23), the target of Pyrazofurin 5'-monophosphate, was increased 3,3-fold over that observed in the plateau-phase tumor cells. In the lethal effect of Pyrazofurin, the growth phase and the increased activity of orotidine 5'-monophosphate decarboxylase play an important role. In the protection of the tumor cells from the drug, the rapid uptake of uridine and cytidine and the high activity and strong affinity of uridine-cytidine kinase towards uridine and cytidine are significant. In the failure of protection by uracil, the slow incorporation of this nucleoside in these hepatoma cells is relevant.

Original languageEnglish
JournalCancer Research
Volume40
Issue number8
Publication statusPublished - 1980

Fingerprint

pyrazofurin
Uridine
Cell Cycle
Cytidine
Hepatocellular Carcinoma
Uracil
Carboxy-Lyases
Uridine Kinase
Growth
Neoplasms
Trichloroacetic Acid
Hypoxanthine
Cytoprotection

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Oláh, E., Lui, M. S., Tzeng, D. Y., & Weber, G. (1980). Phase and cell cycle specificity of pyrazofurin action. Cancer Research, 40(8).

Phase and cell cycle specificity of pyrazofurin action. / Oláh, E.; Lui, M. S.; Tzeng, D. Y.; Weber, G.

In: Cancer Research, Vol. 40, No. 8, 1980.

Research output: Contribution to journalArticle

Oláh, E, Lui, MS, Tzeng, DY & Weber, G 1980, 'Phase and cell cycle specificity of pyrazofurin action', Cancer Research, vol. 40, no. 8.
Oláh, E. ; Lui, M. S. ; Tzeng, D. Y. ; Weber, G. / Phase and cell cycle specificity of pyrazofurin action. In: Cancer Research. 1980 ; Vol. 40, No. 8.
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abstract = "Pyrazofurin killed hepatoma 3924A cells in tissue culture with a 50{\%} lethal dose of 0.4 μM, as determined by the colony-forming ability of the cells after 7-days incubation with the drug. Only in the logarithmic phase of growth were the hepatoma cells sensitive to the cytotoxic action of Pyrazofurin which had no detectable effect on plateau-phase cells. In the logarithmic growth phase, treatment of the culture with Pyrazofurin for 1 or 2 hr resulted in a biphasic dose-response curve. In synchronized tumor cell cultures, it was shown that the cells sensitive to Pyrazofurin were those in early G1 and early and mid-S phases of the cycle. Uridine and cytidine protected hepatoma 3924A cells from the cytotoxic action of Pyrazofurin. In the presence of 0.5 μM Pyrazofurin for 7 days, an equimolar concentration of uridine resulted in 70{\%} survival, and 5 to 10 μM uridine provided complete protection. In the presence of 1 μM Pyrazofurin, cytidine (1.0 m(M)) provided 80{\%} protection, and uridine (0.1 m(M)) resulted in 90{\%} survival; hypoxanthine and uracil were ineffective. In hepatoma 3924A cells, uridine and cytidine were rapidly incorporated into trichloroacetic acid soluble material. Uracil was incorporated at a slower rate. Pyrazofurin enhanced the incorporation of uridine into nucleic acids 2-fold and that of uracil 3-fold. In the logarithmically growing hepatoma cells, the activity of orotidine 5'-monophosphate decarboxylase (EC 4.1.1.23), the target of Pyrazofurin 5'-monophosphate, was increased 3,3-fold over that observed in the plateau-phase tumor cells. In the lethal effect of Pyrazofurin, the growth phase and the increased activity of orotidine 5'-monophosphate decarboxylase play an important role. In the protection of the tumor cells from the drug, the rapid uptake of uridine and cytidine and the high activity and strong affinity of uridine-cytidine kinase towards uridine and cytidine are significant. In the failure of protection by uracil, the slow incorporation of this nucleoside in these hepatoma cells is relevant.",
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