A potent pancreatic carcinogen in Syrian hamsters: N-nitrosobis(2-oxopropyl)amine.

N-Nitrosobis(2-oxopropyl)amine (BOP), a further postulated beta-metabolite of di-n-propylnitrosamine, induced a high incidence of pancreatic duct adenomas and adenocarcinomas as early as 13 weeks in Syrian hamsters receiving weekly sc injections for life and a few pancreatic adenomas, after 28 weeks, in those given a single sc dose. Compared to related compounds, N-nitrosobis(2-hydroxypropyl)amine and N-nitrosobis(2-acetoxy-propyl)amine which are also pancreatic carcinogens, BOP induced only a few neoplasms of the lung, liver, and kidney and none in the nasal cavity, larynx, and trachea. The results therefore indicate progress in developing a more specific model for pancreatic carcinogenesis studies.

Improvement of pancreatic cancer model by modified treatment with N-nitroso-bis (2-oxopropyl) amine.

Comparative studies were conducted in 2 groups of Syrian golden hamsters treated with N-nitroso-bis (2-oxopropyl)amine (BOP) weekly for life (group A) or weekly for 6 weeks (group B), and sacrificed at 2-week intervals. Pancreatic neoplasms developed as early as 8 weeks (group B) and 10 weeks (group A); however, in group B there were fewer, smaller lesions, well-differentiated morphologically. Liver neoplasms occurred only in group A, while gallbladder and kidney tumors were seen in both groups. A lower incidence of pulmonary adenomas was found in group B than in group A, which also had pulmonary carcinomas. The results indicate a further advance in the development of a pancreatic cancer model.

Mutagenicity of beta-oxidized N,N,-di-n-propylnitrosamine derivatives in S. typhimurium mediated by rat and hamster tissues.

The relative abilities of liver, kidney and lung fractions from untreated or phenobarbitone-pretreated rats and hamsters to convert N,N-di-n-propylnitrosamine and several beta-oxidized synthetic putative intermediates into mutagens was quantitatively compared in a tissue-mediated mutagenicity assay with S. typhimurium TA 1530 in vitro. With one exception, namely, N,N-di(2-acetoxy-n-propyl)nitrosamine, liver was the most active tissue from hamsters; in rats also, only liver fractions were able to activate some nitroso-compounds to mutagens. The highest enzyme-mediated mutagenicities were observed with N-2-hydroxy-n-propyl-N-n-propylnitrosamine, N,N-di-n-propylnitrosamine and N,N-di(2-acetoxy-n-propyl)nitrosamine. Hamster lung tissue converted N,N-di-n-propylnitrosamine, N-2-hydroxy-n-propyl-N-n-propylnitrosamine and N,N-di(2-acetoxy-n-propyl)nitrosamine into mutagens; activity with the latter compound was greater with lung tissue than with liver tissue when untreated animals were used. N-methyl-N-n-propylnitrosamine was mutagenic in the presence of hamster liver fraction but less so than N,N-di-n-propylnitrosamine. The results of the mutagenicity assays using various tissues are qualitatively compared to sites of tumour formation in rats and hamsters by these N-nitrosamines.

Influence of disulfiram on the organotropy of the carcinogenic effect of dimethylnitrosamine and diethylnitrosamine in rats.

In former studies in rats and mice it was shown that the acute toxicity of dimethylnitrosamine (DMNA) and diethylnitrosamine (DENA) is reduced by additional treatment with tetraethylthiuramdisulfide [(Disulfiram, Antabus (DSF)]. In long-term experiments in 40 rats given 500 mg/kg DSF/week the substance did not show carcinogenic effects, however, influenced the action of the nitrosamines. DENA, which was administered to 38 rats in a dosage of 20 mg/kg/week, induced liver tumors in 90% of the animals; in 29% besides some precancerous stages predominantly malignant carcinomas of the oesophagus were seen. DMNA when given to 31 rats in a dosage of 4 mg/kg/week induced liver tumours in 55% of the animals. 26 rats were treated with a combination of 500 mg/kg DSF/week and 20 mg/kg DENA/week. In only 31% of the animals of this group liver tumors were found, however, 81% of them besides some precancerous stages showed predominantly carcinomas of the oesophagus. The combination of 500 mg/kg DSF/week and 4 mg/kg DMNA/week induced only 1 liver tumor (=3%) out of a group of 29 animals, whereas 59% of them showed squamous cell carcinomas of the paranasal sinus that were not seen when DMNA was given alone.

Metabolism of nitrosamines in vivo. V Investigation on 14CO2 exhalation, liver RNA labelling and isolation of two metabolites from urine after administration of [2, 5-14C-]dinitrosopiperazine to rats.

The synthesis of N, N'-dinitrosopiperazine and N-nitrosopiperazine, both 14C-labelled in the 2-and 5-position is described. After i.p. application of 10 mg/69.5 muCi/kg[2, 5-14C]-N, N'-dinitrosopiperazine to rats no labelled 7-methylguanine was detected in the liver RNA; 1% of the radioactivity was exhaled as 14CO2, 1% excreted via the bile and about 40% excreted in the urine. Two of the urine metabolites were identified as 3-hydroxynitrosopyrrolidine and 1-nitrosopiperazinone-(3).

Carcinogenicity of 4-hydroxybutyl-butylnitrosamine in Syrian hamsters.

4-Hydroxybutyl-butylnitrosamine (HBBN), a urinary metabolite of dibutylnitrosamine (DBN) was shown to induce respiratory and bile duct tumors as well as carcinomas of the urinary bladder in Syrian golden hamsters. This contrasts with results previously obtained in rats and demonstrates that HBBN is not a specific bladder carcinogen. Bronchogenic tumors, seen in DBN-treated hamsters, were not observed after injection of HBBN.

A new approach for induction of pancreatic neoplasms.

Weekly s.c. injections of equitoxic doses of 2-hydroxy-propyl-n-propylnitrosamine, 2-oxopropyl-n-propylnitrosamine, and methyl-n-propylnitrosamine, assumed metabolites of di-n-propylnitrosamine by beta oxidation, induced low incidences of pancreatic duct adenomas in Syrian golden hamsters. Di-n-propylnitrosamine did not. Application of 2,2'-dihydroxydi-n-propylnitrosamine, another postulated intermediate of di-n-propylnitrosamine, led to development of various types of pancreatic duct adenomas and ductal carcinomas in high percentages of hamsters. In addition, a few acinar-cell carcinomas were found. The morphology of these neoplasms, their latencies, and their distribution in the different segments of the pancreas are described.

Pancreatic neoplasms in an animal model: morphological, biological, and comparative studies.

After a short latency (15 weeks), a 100% incidence of pancreatic neoplasms was induced in Syrian golden hamsters, following the administration of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN). Data extracted from reports of human pancreatic neoplasms were compared with findings relative to the induced neoplasms. The latter resembled human pancreatic tumors, in both biological and morphological aspects.

Carcinogenic effects of Di-n-propylnitrosamine, beta-hydroxypropyl-n-propylnitrosamine, and methyl-n-propylnitrosamine on Sprague-Dawlay rats.

The carcinogenic effects of di-n-propylnitrosamine and its two related compounds, beta-hydroxypropyl-n-propylnitrosamine (HPPN) and methyl-n-propylnitrosamine (MPN), were tested in rats and compared. All three substances induced neoplasms in the nasal and paranasal cavities, esophagus, and liver. MPN treatment caused the highest tumor incidence in the esophagus, whereas HPPN induced the most hepatic tumors.

Effect of beta-oxidized nitrosamines on syrian hamsters. III. 2,2'-Dihydroxydi-n-propylnitrosamine.

2, 2-Dihydroxy-di-n-propylnitrosamine (DHPN), an assumed metabolite of di-n-propylnitrosamine (DPN), injected subcutaneously once weekly for life, was carcinogenic in Syrian hamsters. The main target organs were the respiratory tract, pancreas, liver, and kidneys. In the respiratory system the most affected segments were the nasal cavities and the lungs. Adenomas and adenocarcinomas, mostly of ductal origin, were induced in the pancreas. Liver neoplasms were hemangloendotheliomas, angiosarcomas, hepatocellular adenomas, cholangiomas, and cholangiocarcinomas. Kidney neoplasms were adenomas and adenocarcinomas. The morphology of the induced neoplasms was described, as well as the effects of DHPN, compared to those another possible metabolite of DPN, 2-hydroxypropyl-n-propylnitrosamine (2-HPPN), which is formed in vivo with only 1 aliphatic chain degraded via theta-oxidation.

Metabolism of nitrosamines in vivo IV. Isolation of 3-hydroxy-1-nitrosopyrrolidine from rat urine after application of 1-nitrosopyrrolidine.

After i. p. application of 6 mg/30 muCi/kg 2,5- and 3,4--14C-nitrosopyrrolidine about 20% of the radioactivity is exhaled as 14-CO2 and about 7% is found in the urine. One of the urinary metabolites was identified by thin layer chromatography, combined GC/MS spectrometry and ultraviolet absorption as 3-hydroxy-1-nitrosopyrrolidine.

Cancer of the pancreas induced in the Syrian golden hamster.

A high incidence of pancreatic neoplasms was induced in Syrian golden hamsters following subcutaneous applications of diisopropanolnitrosamine (DIPN) once weekly for life. The tumor latency was as short as 15 weeks. In clinical and morphologic aspects the induced pancreatic tumors closely resembled those of humans.