Summary
To investigate the role of monomethyltriazenes as the active metabolites of antitumor dimethyltriazenes, the in vivo simultaneous treatment with an inducer (phenobarbital, PB) or an inhibitor (carbon tetrachloride, CCl4) of hepatic drug metabolism was examined in mice bearing Lewis lung carcinoma. Treatment with PB or CCl4 with the dosage and schedules employed proved to be effective in markedly modifying the N-demethylation of the three dimethyltriazenes tested, as had been determined in vitro. No unambiguous increase by PB, or decrease by CCl4, which might theoretically be expected if metabolic conversion to monomethyltriazenes was involved, was observed for the antitumor and antimetastatic activity of dimethyl-triazenes. At the same time, a difference was noted between the effects on primary tumors and those on metastases. These data support the view that generalizations on the relevance of monomethyltriazenes as the active metabolites responsible for the antitumor and antimetastatic activity of dimethyltriazenes may not be valid.
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Abel G, Connors TA, Giraldi T (1977) In vitro metabolic activation of 1-p-carboxamidophenyl-3,3-dimethyltriazene to cytotoxic products. Cancer Lett 3: 259
Audette RCS, Connors TA, Mandel HG, Merai K, Ross WCJ (1973) Studies on the mechanism of action of the tumor inhibitory triazenes. Biochem Pharmacol 22: 1855
Bartoli-Klugman F, Pani B, Babudri N, Monti-Bragadin C, Tamaro M, Venturini S (1982) In vitro mutagenic activity of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) in eukaryotic and prokaryotic cells. Carcinogenesis 3: 467
Beal DD, Skibba JL, Croft WA, Cohen SM, Bryan GT (1975) Carcinogenicity of the antineoplastic agent 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats. J Natl Cancer Inst 54: 951
Cochin J, Axelrod J (1958) Biochemical and pharmacological changes in the rat following chronic administration of morphine, nalorphine and normorphine. J Pharmacol Exp Ther 125: 105
Connors TA, Goddard PM, Merai K, Ross WCJ, Wilman DEV (1976) Tumor inhibitory triazenes: structural requirements for an active metabolite. Biochem Pharmacol 25: 241
DeMatteis F (1982) Loss of microsomal components in druginduced liver damage, in cholestasis and after administration of chemical which stimulate heme catabolism. In: Shenkenan JB, Kupfer D (eds) Hepatic cytochrome P-450 monooxygenase system. Pergamon, Oxford, pp 307–340
Druckrey H (1973) Specific carcinogenic and teratogenic effects of indirect alkylating methyl and ethyl compounds, and their dependency on stages of ontogenic developments. Xenobiotica 3: 271
Elks J, Heyd DH (1943) Union of aryl nuclei: VI. Reactions with 1-aryl-3,3-dimethyltriazenes. J Chem Soc: 441
Giraldi T, Nisi C, Sava G (1975) Investigation on the oxidative N-demethylation of aryltriazenes in vitro. Biochem Pharmacol 24: 1793
Giraldi T, Nisi C, Connors TA, Goddard PM (1977) Preparation and antitumor activity of 1-aryl-3,3-dimethyltriazene derivatives. J Med Chem 20: 850
Giraldi T, Guarino AM, Nisi C, Sava G (1980) Antitumor and antimetastatic effects of benzenoid triazenes in mice bearing Lewis lung carcinoma. Pharmacol Res Commun 12: 1
Hano K, Akashi A, Yamamoto I, Narumi S, Iwata H (1968) Further investigation on the carcinostatic activity of 4(or 5)-aminoimidazole-5(or 4)-carboxamide derivatives: structureactivity relationship. Gann 59: 207
Hansch C, Smith N, Engle R, Wood H (1972) Quantitative structure-activity relationship of antineoplastic drugs: nitrosoureas and triazenoimidazoles. Cancer Chemother Rep [1] 56: 443
Klages F, Mesch W (1955) Addition reactions of triazenes, illustrating the reactivity of N=N double bonds. Chem Ber 88: 388
Kleinhues P, Kolar GF, Margison GP (1976) Interaction of the carcinogen 3,3-dimethyl-1-phenyltriazene with nucleic acids of various rat tissues and the effect of a protein-free diet. Cancer Res 36: 2189
Kohlsmith DJ, Vaughan K, Luner SJ (1984) Triazene metabolism: III. In vitro cytotoxicity towards M21 cells and in vivo antitumor activity of the proposed metabolites of the antitumor 1-aryl-3,3-dimethyltriazenes. J Can Physiol Pharmacol 62: 396
Kolar GF (1972) Synthesis of biologically active triazenes from isolable diazonium salts. Z Naturforsch [B] 27: 1183
Kolar GF, Fahrig R, Vogel E (1974) Structure-activity dependence in some novel ring substituted 3,3-dimethyl-1-phenyltriazenes. Genetic effects in Drosophila melanogaster and in Saccharomyces cerevisiae by a direct and host-mediated assay. Chem Biol Interact 9: 365
Lassiani L, Nisi C, Sava G, Giraldi T (1983) Synthesis and antitumor activity of N-(3,3-dimethyl-1-triazeno)benzoylaminoacids. Eur J Med Chem [Chim Ther] 18: 401
Lassiani L, Nisi C, Giraldi T, Sava G, Cuman R (1984) Selective antimetastatic triazenes: a quantitative approach. Quant Struct Act Relat 3: 59
Lineweaver, Burk D (1934) The determination of enzyme dissociation constants. J Am Chem Soc 56: 658
Litchfield J, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96: 99
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265
Malaveille C, Kolar GF, Bartsch H (1976) Rat and mouse tissue-mediated mutagenicity of ring substituted 3,3-dimethyl-1-phenyltriazenes in Salmonella typhimurium. Mutat Res 36: 1
Nardelli B, Contessa AR, Romani L, Sava G, Nisi C, Fioretti MC (1984) Antigenic changes of murine lymphoma cells following in vitro treatment with aryl-triazene derivatives. Cancer Immunol Immunother 16: 157
Preussmann R, Ivankovic S, Landschutz C, Gimmy J, Flohr E, Griesbach U (1974) Carcinogene Wirkung von 13 Aryldialkyltriazenen an BD Ratten. Z Krebsforsch 81: 285
Puccetti P, Romani L, Fioretti MC (1985) Chemical Xenogenization of tumor cells. Trends Pharmacol Sci 6: 485
Rutty CJ, Newell DR, Vincent RB, Abel G, Goddard PM, Harland SJ, Calvert AH (1983) The species-dependent pharmacokinetics of DTIC. Br J Cancer 48: 140
Sava G, Giraldi T, Lassiani L, Nisi C (1982) Metabolism and mechanism of the antileukemic action of isomeric aryldimethyltriazenes. Cancer Treat Rep 68: 1751
Sava G, Giraldi T, Lassiani L, Nisi C, Farmer PB (1982) Mechanism of the antileukemic effects of 1-p-carboxamidophenyl-3,3-dimethyltriazene and its in vitro metabolites. Biochem Pharmacol 31: 3629
Sava G, Giraldi T, Lassiani L, Dogani R (1983) Effects of isomeric aryldimethyltriazenes on Lewis lung carcinoma growth and metastasis in mice. Chem Biol Interact 46: 131
Sava G, Giraldi T, Zupi G, Sacchi A (1984) Effects of antimetastatic dimethyltriazenes in mice bearing Lewis lung carcinoma lines with different metastatic potential. Invasion Metastasis 4: 171
Snyder R, Renner H (1982) Classes of hepatic microsomal mixed function oxidase inducers. In: Shenkenan JB, Kupfer D (eds) Hepatic cytochrome P-450 monooxygenase system. Pergamon, Oxford, pp 227–260
Sokal RR, Rohlf FJ (1969) In: Biometry, the principles and practice of statistics in biological research. Freeman, San Francisco, pp 201–252
Venger HB, Hansch C, Hatleway GJ, Aurein YU (1979) Ames test of 1-(X-phenyl)-3,3-dialkyltriazenes. A quantitative structure-activity study. J Med Chem 22: 473
Vogel E, Fahrig R, Obe G (1973) Triazenes, a new group of indirect mutagens; comparative investigations on the genetic effects of different aryldialkyltriazenes using Saccharomyces cerevisiae the host-mediated assay, Drosophila melanogaster, and human chromosomes in vitro. Mutat Res 21: 123
Wilman DEV, Cox PJ, Goddard PM, Hart LI, Merai K, Newell DR (1984) Tumor inhibitory triazenes: 3. Dealkylation within an homologous series and its relation to antitumor activity. J Med Chem 27: 870
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This work was supported by a grant from the Italian National Research Council, Special Project ‘Oncology’, contract no. 85.02186.44 and one from the Italian Ministry of Education (MPI)
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Sava, G., Zorzet, S., Perissin, L. et al. Effects of an inducer and an inhibitor of hepatic metabolism on the antitumor action of dimethyltriazenes. Cancer Chemother. Pharmacol. 21, 241–245 (1988). https://doi.org/10.1007/BF00262778
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DOI: https://doi.org/10.1007/BF00262778