Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide)

M. S. Lui, M. A. Faderan, J. J. Liepnieks, Y. Natsumeda, E. Oláh, H. N. Jayaram, G. Weber

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Abstract

Tiazofurin, a C-nucleoside, was cytotoxic in hepatoma 3924A cells grown in culture with an LC50 = 7.5 μM. In the culture, a closely linked dose-related response of tumor cell-kill and depletion of GTP pools was observed after tiazofurin treatment. In rats carrying subcutaneously transplanted hepatoma 3924A solid tumors, a single intraperitoneal injection of tiazofurin (200 mg/kg) caused a rapid inhibition of IMP dehydrogenase (EC 1.2.1.14) activity and depleted GDP, GTP, and dGTP pools in the tumor; concurrently, the 5-phosphoribosyl 1-pyrophosphate (PRPP) and IMP pools expanded 8- and 15-fold, respectively. Tiazofurin decreased tumoral IMP dehydrogenase activity and dGTP pools in a dose-dependent manner over a range of 50-200 mg/kg; by contrast, the depletion of GTP and the accumulation of IMP and PRPP pools were near maximum at 50 mg/kg. The increase in PRPP pools may be attributed to an inhibition by IMP of the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8). The IMP dehydrogenase activity and the pools of ribonucleotides returned to the normal range by 24-48 h after the single injection of tiazofurin. However, the markedly depleted dGTP pools remained low for 72 h. Tiazofurin treatment resulted in significant anti-tumor activity in rats inoculated with hepatoma 3924A. The decrease in GTP levels and particularly the sustained depletion in the dGTP pools may explain, in part at least, the chemotherapeutic action of tiazofurin on hepatoma 3924A. This is the first report showing that a marked therapeutic response was achieved against rapidly growing hepatoma 3924A by treatment with a single anti-metabolite.

Original languageEnglish
Pages (from-to)5078-5082
Number of pages5
JournalJournal of Biological Chemistry
Volume259
Issue number8
Publication statusPublished - 1984

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tiazofurin
IMP Dehydrogenase
Metabolism
Modulation
Phosphoribosyl Pyrophosphate
Hepatocellular Carcinoma
Guanosine Triphosphate
Inosine Monophosphate
Tumors
Rats
Neoplasms
Cells
Ribonucleotides
Hypoxanthine Phosphoribosyltransferase
Therapeutics
Metabolites
Intraperitoneal Injections
Nucleosides
Cell culture
Reference Values

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lui, M. S., Faderan, M. A., Liepnieks, J. J., Natsumeda, Y., Oláh, E., Jayaram, H. N., & Weber, G. (1984). Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide). Journal of Biological Chemistry, 259(8), 5078-5082.

Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide). / Lui, M. S.; Faderan, M. A.; Liepnieks, J. J.; Natsumeda, Y.; Oláh, E.; Jayaram, H. N.; Weber, G.

In: Journal of Biological Chemistry, Vol. 259, No. 8, 1984, p. 5078-5082.

Research output: Contribution to journalArticle

Lui, MS, Faderan, MA, Liepnieks, JJ, Natsumeda, Y, Oláh, E, Jayaram, HN & Weber, G 1984, 'Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide)', Journal of Biological Chemistry, vol. 259, no. 8, pp. 5078-5082.
Lui, M. S. ; Faderan, M. A. ; Liepnieks, J. J. ; Natsumeda, Y. ; Oláh, E. ; Jayaram, H. N. ; Weber, G. / Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide). In: Journal of Biological Chemistry. 1984 ; Vol. 259, No. 8. pp. 5078-5082.
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AU - Liepnieks, J. J.

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AU - Oláh, E.

AU - Jayaram, H. N.

AU - Weber, G.

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