Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1979 Nov;40(5):768–773. doi: 10.1038/bjc.1979.259

The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells.

P G Larsson, F Haffner, G O Brłnstad, T Christoffersen
PMCID: PMC2010101  PMID: 228692

Abstract

The antitumour agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) was found to inhibit competitively the low-Km cyclic AMP phosphodiesterase activity in an ammonium-sulphate-precipitable fraction of the 2,000g supernatant of rat liver. With substrate concentration at 0.25 microM, I50 was 790 microM for DTIC and 350 microM for theophylline. DTIC at 2 mM more than doubled the cAMP response to glucagon in hepatocytes and to adrenaline in MH1C1 hepatoma cells, indicating that it also exerts its inhibitory effect on the phosphodiesterase in intact cells. The possible contribution of the phosphodiesterase inhibition to the growth-inhibitory and cytotoxic effects of DTIC is discussed.

Full text

PDF
768

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beal D. D., Skibba J. L., Whitnable K. K., Bryan G. T. Effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide and its metabolites on Novikoff hepatoma cells. Cancer Res. 1976 Aug;36(8):2827–2831. [PubMed] [Google Scholar]
  2. Berg T., Boman D., Seglen P. O. Induction of tryptophan oxygenase in primary rat liver cell suspensions by glucocorticoid hormone. Exp Cell Res. 1972 Jun;72(2):571–574. doi: 10.1016/0014-4827(72)90034-1. [DOI] [PubMed] [Google Scholar]
  3. Bono V. H., Jr Studies on the mechanism of action of DTIC (NSC-45388). Cancer Treat Rep. 1976 Feb;60(2):141–148. [PubMed] [Google Scholar]
  4. Christoffersen T., Berg T. Altered hormone control of cyclic AMP formation in isolated parenchymal liver cells from rats treated with 2-acetylaminofluorene. Biochim Biophys Acta. 1975 Jan 13;381(1):72–77. doi: 10.1016/0304-4165(75)90190-7. [DOI] [PubMed] [Google Scholar]
  5. Christoffersen T., Morland J., Osnes J. B., Oye I. Development of cyclic AMP metabolism in rat liver. A correlative study of tissue levels of cyclic AMP, accumulation of cyclic AMP in slices, adenylate cyclase activity and cyclic nucleotide phosphodiesterase activity. Biochim Biophys Acta. 1973 Jul 28;313(2):338–349. doi: 10.1016/0304-4165(73)90033-0. [DOI] [PubMed] [Google Scholar]
  6. Culver B., Sahu S. K., Vernadakis A., Prasad K. N. Effects of 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide [NSC 45388, DTIC] on neuroblastoma cells in culture. Biochem Biophys Res Commun. 1977 Jun 6;76(3):778–783. doi: 10.1016/0006-291x(77)91568-6. [DOI] [PubMed] [Google Scholar]
  7. Frandsen E. K., Krishna G. A simple ultrasensitive method for the assay of cyclic AMP and cyclic GMP in tissues. Life Sci. 1976 Mar 1;18(5):529–541. doi: 10.1016/0024-3205(76)90331-3. [DOI] [PubMed] [Google Scholar]
  8. Friedman D. L. Role of cyclic nucleotides in cell growth and differentiation. Physiol Rev. 1976 Oct;56(4):652–708. doi: 10.1152/physrev.1976.56.4.652. [DOI] [PubMed] [Google Scholar]
  9. Gerulath A. H., Barranco S. C., Humphrey R. M. The effects of treatments with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide in darkness and in light on survival and progression in Chinese hamster ovary cells in vitro. Cancer Res. 1974 Aug;34(8):1921–1925. [PubMed] [Google Scholar]
  10. Gerulath A. H., Loo T. L. Mechanism of action of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide in mammalian cells in culture. Biochem Pharmacol. 1972 Sep 1;21(17):2335–2343. doi: 10.1016/0006-2952(72)90384-x. [DOI] [PubMed] [Google Scholar]
  11. Harper J. F., Brooker G. Femtomole sensitive radioimmunoassay for cyclic AMP and cyclic GMP after 2'0 acetylation by acetic anhydride in aqueous solution. J Cyclic Nucleotide Res. 1975;1(4):207–218. [PubMed] [Google Scholar]
  12. Kotani M., Koizumi Y., Yamada T., Kawasaki A., Akabane T. Increase of cyclic adenosine 3':5'-monophosphate concentration in transplantable lymphoma cells by vinca alkaloids. Cancer Res. 1978 Sep;38(9):3094–3099. [PubMed] [Google Scholar]
  13. Loo T. L., Housholder G. E., Gerulath A. H., Saunders P. H., Farquhar D. Mechanism of action and pharmacology studies with DTIC (NSC-45388). Cancer Treat Rep. 1976 Feb;60(2):149–152. [PubMed] [Google Scholar]
  14. Loo T. L., Luce J. K., Jardine J. H., Frei E., 3rd Pharmacologic studies of the antitumor agent 5-(dimethyltriazeno)imidazole-4-carboxamide. Cancer Res. 1968 Dec;28(12):2448–2453. [PubMed] [Google Scholar]
  15. Pastan I. H., Johnson G. S., Anderson W. B. Role of cyclic nucleotides in growth control. Annu Rev Biochem. 1975;44:491–522. doi: 10.1146/annurev.bi.44.070175.002423. [DOI] [PubMed] [Google Scholar]
  16. Prasad K. N. Differentiation of neuroblastoma cells in culture. Biol Rev Camb Philos Soc. 1975 May;50(2):129–165. doi: 10.1111/j.1469-185x.1975.tb01055.x. [DOI] [PubMed] [Google Scholar]
  17. Richardson U. I., Tashjian A. H., Jr, Levine L. Establishment of a clonal strain of hepatoma cells which secrete albumin. J Cell Biol. 1969 Jan;40(1):236–247. doi: 10.1083/jcb.40.1.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rudolph S. A., Greengard P., Malawista S. E. Effects of colchicine on cyclic AMP levels in human leukocytes. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3404–3408. doi: 10.1073/pnas.74.8.3404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Seglen P. O. Preparation of rat liver cells. I. Effect of Ca 2+ on enzymatic dispersion of isolated, perfused liver. Exp Cell Res. 1972 Oct;74(2):450–454. doi: 10.1016/0014-4827(72)90400-4. [DOI] [PubMed] [Google Scholar]
  20. Skibba J. L., Beal D. D., Ramirez G., Bryan G. T. N-demethylation the antineoplastic agent4(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)-carboxamide by rats and man. Cancer Res. 1970 Jan;30(1):147–150. [PubMed] [Google Scholar]
  21. Steiner A. L., Kipnis D. M., Utiger R., Parker C. Radioimmunoassay for the measurement of adenosine 3',5'-cyclic phosphate. Proc Natl Acad Sci U S A. 1969 Sep;64(1):367–373. doi: 10.1073/pnas.64.1.367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tihon C., Goren M. B., Spitz E., Rickenberg H. V. Convenient elimination of trichloroacetic acid prior to radioimmunoassay of cyclic nucleotides. Anal Biochem. 1977 Jun;80(2):652–653. doi: 10.1016/0003-2697(77)90693-5. [DOI] [PubMed] [Google Scholar]
  23. Tisdale M. J., Phillips B. J. Adenosine 3',5'-monophosphate phosphodiesterase activity in experimental animal tumours which are either sensitive or resistant to bifunctional alkylating agents. Biochem Pharmacol. 1975 Jan 15;24(2):205–210. doi: 10.1016/0006-2952(75)90278-6. [DOI] [PubMed] [Google Scholar]
  24. Tisdale M. J., Phillips B. J. Comparative effects of alkylating agents and other anti-tumour agents on the intracellular level of adenosine 3',5'-monophosphate in Walker carcinoma. Biochem Pharmacol. 1975 Jul 15;24(13-14):1271–1276. doi: 10.1016/0006-2952(75)90335-4. [DOI] [PubMed] [Google Scholar]
  25. Tisdale M. J. The reaction of alkylating agents with cyclic 3',5'-nucleotide phosphodiesterase. Chem Biol Interact. 1974 Aug;9(2):145–153. doi: 10.1016/0009-2797(74)90006-4. [DOI] [PubMed] [Google Scholar]
  26. Yamamoto I. 4 (or 5)-diazoimidazole-5 (or 4)-carboxamide and related triazenoimidazoles as antibacterial agents: their effects on nucleic acid metabolism of Escherichia coli B. Biochem Pharmacol. 1969 Jun;18(6):1463–1472. doi: 10.1016/0006-2952(69)90260-3. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES