Mechanism of carcinogenesis with 1-Aryl-3,3-dialkyltriazenes. Enzymatic dealkylation by rat liver microsomal fraction in vitro

Preußmann, R.; Hodenberg, A. von; Hengy, H

doi:10.1016/0006-2952(69)90002-1

Cited by 106 publications

(17 citation statements)

References 25 publications

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“…3,3-Dimethyl-1-phenyltriazene (DMPT) is a nethylating agent that is mutagenic ( 11,28,41,46), teratogenic (18, 34), and carcinogenic (16,40). As a teratogen, DMPT has a remarkable lack of phase specificity in that the targets are not significantly influenced by administration on different days of gestation (Frank, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

et al. 1992

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Exposure of rat embryos to 3,3-dimethyl-1-phenyltriazene (DMPT) results in numerous malformations, but the urogenital system is not affected. In contrast, exposure of rat fetuses to DMPT has been reported to result in renal neoplasms, which were not further classified. To better understand this discrepancy in organotropism of the teratogenic and transplacental carcinogenic processes, the present study was undertaken to characterize the neoplasms induced in rat fetuses exposed to DMPT in utero. Renal neoplasms and persistent mesenchyme were observed in 19.2 and 11.5%, respectively, of the offspring of rats treated with 1 mg DMPT/ kg body weight intraperitoneally on gestation days 16, 18, and 20. The majority of these renal lesions were observed in females. The renal neoplasms were mixtures of various types of mesenchymal tissue derivatives including smooth muscle and fibrous connective tissue. These neoplasms would be classified as renal mesenchymal tumors in rats. Brain neoplasms (numerous types), compound odontomas, and micrognathism were observed predominantly in male offspring from the same group. This treatment also resulted in decreased body weights, increased incidence of sudden loss of body weight, tremors and ataxia, and hypoplastic testes. Exposure to single intraperitoneal doses of DMPT on gestation day 20 did not produce a classic dose-response pattern: Minimal effects were observed with 10 mg DMPT/kg (occasional renal mesenchymal tumors and brain neoplasms), marked effects were observed with 30 mg DMPT/kg (lower incidence rate of most of the alterations observed with 1 mg/kg on gestation days 16, 18, and 20), and no effects were observed with 60 mg DMPT/kg. DMPT administered intraperitoneally at 1 mg/kg body weight on gestation days 16, 18, and 20 is an animal model of transplacental chemically induced renal neoplasms, which provide lesions with similarities to both intralobar nephrogenic rests and congenital mesoblastic nephroma of humans. Why the kidney is a carcinogenic target and not a teratogenic target remains unknown.

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Section: Introductionmentioning

confidence: 99%

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

et al. 1992

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“…Therefore the physical state (suspension versus solution) and the presence of peanut oil do not interfere with the DMITI phenomenon which follows DTIC treatment. The use of a drug suspension in oil was selected since the aryl-monomethyl-triazenes have a very short half-life of hydrolysis of the triazene group (Table 1) when dissolved in media containing water [10]. Figure 1 also shows the effect of treatment with MM-NO2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Antigenic changes of a murine lymphoma by in vivo treatment with triazene derivatives

Fioretti

Nardelli

Bianchi

et al. 1981

Cancer Immunol Immunother

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ancer l mmunologyand i l lnmunotherapy © Springer-Verlag 1981 Summary. Five aryltriazenes were studied for efficacy in mediating immunogenic changes of tumor cells by in vivo treatment of lymphoma-bearing mice. It was found that four analog compounds produced increase in cell immunogenicity similar to that described for 5-(3,3-dimethyl-l -triazeno)-imidazole-4-carboxamide (DTIC), one of the five being by contrast completely inactive. Moreover, the use of a drug-resistant lymphoma illustrates that cytotoxic activity is not mandatory for the appearance of the immunogenic changes. The results show that a drug-mediated increase of tumor immunogenicity (DMITI) can be induced by triazene derivatives not containing the imidazole moiety.of triazene compounds have been reported in the literature [3,8], but similar data on the generation of DMITI are lacking.The present paper deals with studies on the efficacy of aryltriazenes in mediating the immunogenic changes of tumor cells by in vivo treatment of lymphoma-bearing mice.The results show that the imidazole moiety present in DTIC is presumably not directly responsible for the generation of DMITI, since four analog triazene derivatives not containing the imidazole ring produced effects on cellular immunogenicity similar to those described for DTIC.

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“…The compound 5-(dimethyltriazeno)-imidazole-4-carboxamide, (III) , is also absorbed erratically in the gastrointestinal tract (Loo et al, 1967;Loo, Luce, Jardine & Frei, 1968), but it is clinically more useful than compound (I) in inducing temporary remission of malignant melanoma (Shealy, Montgomery & Lafter, 1962;Loo, 1971). Many authors have assumed that the mechanism of the anticancer activity of these compounds is similar to the mechanism of carcinogenesis of aryltriazenes proposed by Preussman, von Hodenberg & Hengy (1969). These workers suggested that the aryl-triazenes ultimately degrade to a carbonium ion plus other products with the carbonium ion being responsible for the alkylating properties of these compounds.…”

Section: Introductionmentioning

confidence: 91%

Chemotherapeutic agents. The structure of 1-(2-chloroethyl)-3-(4-carbamoylpyrazol-3-yl)-Δ²-1,2,3-triazolinium chloride

Whinnery¹,

Watson²

1972

Acta Crystallogr Sect B

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A number of nitrogen mustards have shown significant activity in experimental tumors; however, many of them exhibit erratic behavior in clinical tests. The nitrogen mustard 5-[3,3-bis(2-chloroethyl)-l-triazeno]-pyrazole-4-carboxamide was found to undergo a spontaneous ring closure to form the compound 1-(2-chloroethyl)-3-(4-carbamoylpyrazol-3-yl)-A 2-1,2,3-triazolinium chloride, [CION6CaHI2] ÷ CI -, which shows no in vivo activity in experimental tumors. The structure of this ionic compound was determined by single-crystal X-ray diffraction techniques, using 1253 independent counter-collected reflections. A full-matrix least-squares refinement yielded a conventional R value of 0-0497. The space group is Pbca and the cell dimensions are a= 14.151 (5), b= 16-990 (5) and c= 10.344 (10) ~. The observed density of 1.489 g.cm -3 is consistent with 8 molecules per unit cell, de= 1.490 g.cm -3. The molecule contains a positively charged triazolinium ring with the chloride ion almost symmetrically located above the ring. The planes of the pyrazole and triazolinium rings make an angle of 50 ° while the amide group makes an angle of 22 ° with the pyrazole ring. The amide oxygen atom interacts with the triazolinium ring but on the side opposite to the chloride ion. Both pyrazole tautomers are present in the crystal.

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Mechanism of carcinogenesis with 1-Aryl-3,3-dialkyltriazenes. Enzymatic dealkylation by rat liver microsomal fraction in vitro

Cited by 106 publications

References 25 publications

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

Antigenic changes of a murine lymphoma by in vivo treatment with triazene derivatives

Chemotherapeutic agents. The structure of 1-(2-chloroethyl)-3-(4-carbamoylpyrazol-3-yl)-Δ²-1,2,3-triazolinium chloride

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Mechanism of carcinogenesis with 1-Aryl-3,3-dialkyltriazenes. Enzymatic dealkylation by rat liver microsomal fraction in vitro

Cited by 106 publications

References 25 publications

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

Antigenic changes of a murine lymphoma by in vivo treatment with triazene derivatives

Chemotherapeutic agents. The structure of 1-(2-chloroethyl)-3-(4-carbamoylpyrazol-3-yl)-Δ2-1,2,3-triazolinium chloride

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Chemotherapeutic agents. The structure of 1-(2-chloroethyl)-3-(4-carbamoylpyrazol-3-yl)-Δ²-1,2,3-triazolinium chloride