Carcinogenicity of methylated derivatives of N-nitrosodiethylamine and related compounds in Sprague-Dawley rats.

Five nitrosamines, which can be considered alkyl derivatives of N-nitrosodiethylamine, were tested for carcinogenicity by administration to Sprague-Dawley rats in drinking water at approximately equimolar concentrations. N-Nitrosodi-n-propylamine was a potent carcinogen but less so than N-nitrosodiethylamine and gave the same spectrum of tumors. N-Nitrosodiisopropylamine was very much weaker than N-nitrosodiethylamine and induced only tumors of the nasal turbinates in significant incidence. At the doses given, neither N-nitrosodiisobutylamine nor N-nitrosodi-sec-butylamine was significantly carcinogenic. In contrast, the cyclic nitrosamine N-nitrosohexamethyleneimine was equally potent with N-nitrosodiethylamine and gave the same spectrum of tumors in liver, esophagus, and nasal turbinates. The results support the concept that oxidation at the alpha carbon atom of nitrosamines is a significant step in carcinogenesis.     

Caffeine-derived N-nitroso compounds. V. Carcinogenicity of mononitrosocaffeidine and dinitrosocaffeidine in bd-ix rats

Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N- nitroso compounds obtained from in vitro nitrosation of caffeidine, a hydrolysis product of caffeine present in a typically made and widely consumed tea from Kashmir (India), a high incidence area of esophageal and stomach cancer. The chemical synthesis, in vitro metabolic studies and mutagenicity of the compounds has been previously reported. DNC, a nitrosamide is highly mutagenic both with and without metabolic activation whereas MNC, like several other aromatic asymmetric nitrosamines, does not exhibit genotoxic or mutagenic properties. We now report the results of the first carcinogenicity experiments on chronic oral administration of these compounds in BD-IX rats. The acute LD50 of MNC and DNC were about 1300 and 230 mg/kg b.w., respectively. Lung oedema and gastrointestinal haemorrhages were the first symptoms of intoxication observed after 2 days for both the compounds. All three dose groups of MNC treated rats showed localization of tumours in nasal cavity (93.9-100% of all malignant tumours). The tumours were histologically diagnosed as neuroepitheliomas of the olfactory epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell carcinoma of the nasal cavity in the ratio of 3:1. No tumours of the nasal cavity were observed in the untreated controls. DNC, in contrast, induced squamous cell carcinoma of forestomach in 100% animals at low and high doses, of which nearly half the tumours metastasized predominantly into the peritoneum. No forestomach tumours were seen in the untreated controls. The data presented here clearly show the potential for induction of malignant tumours and distinct organ- specificity by MNC and DNC in rats, and support the postulate that a chronic exposure to these compounds may provide a carcinogenic risk for high incidence of gastrointestinal cancers in Kashmir.      

Carcinogenicity of N-nitroso compounds. Species and route differences in regard to organotropism

N-nitroso compounds were found to be carcinogenic in 22 animals species. The organotropism of the carcinogenic action may be related to a variety of organs and organ systems. It does not only depend on the chemical structure of the molecules but also on the daily dose. It is highly probable that N-nitroso compounds also act carcinogenically in human beings. Predictions as to the organotropism of the carcinogenic action in man cannot be made. N-nitroso compounds have to be regarded as 'multipotent'.     

New vinca alkaloids and related compounds.

The vinca alkaloids remain among the most useful classes of anticancer agents used in the clinic today. However, previous analogs of these agents have not realized either increased safety or an enhanced antitumor spectrum. Currently, three derivatives are in clinical trial: vinorelbine, vintripol, and vinxaltine. Vinorelbine has shown consistent antitumor activity in patients with breast carcinoma and is in phase III trials in the United States, Europe, and Japan. Vintripol and vinxaltine, vinca alkaloids conjugated to amino acids, are in early clinical trials in Europe. The dose-limiting toxicity of these agents is leukopenia. A similar agent with a different chemical structure, rhizoxin, is in early phase II clinical trials with initial activity noted in breast carcinoma. The ultimate role of these agents in treatment of human malignancy awaits the results of ongoing studies.     

Carcinogenicity in rats of the mutagenic compounds 1-nitropyrene and 3-nitrofluoranthene

1-Nitropyrene and 3-nitrofluoranthene are present in diesel exhaust, in pollutants in air, and were also present in certain xerographic toners and copies. Their carcinogenicities were studied in male F344/DuCrj rats by subcutaneous injection. Sarcomas, mainly malignant fibrous histiocytomas at the site of injection were induced in 8 to 17 (47%) rats by 1-nitropyrene and in 4 of 10 (40%) rats by 3-nitrofluoranthene. Some tumors were serially transplantable in the same strain of rats.     

Carcinogenicity of methylated nitrosopiperidines.

The carcinogenicity of nitrosopiperidine and five methylated derivatives was compared by feeding them to rats at equimolar concentrations in drinking water, at the rate of 20 ml per day, 5 days a week. The maximum treatment time was 50 weeks. Nitrosopiperidine, 2-methyl-, 3-methyl- and 4-methyl-nitrosopiperidine induced tumors of the nasal turbinates or upper gastrointestinal tract in almost 100% of the animals. There was a significantly longer time to death from these tumors in the group treated with 2-methylnitrosopiperidine and a number of hepatocellular carcinomas appeared in this longer lived group. Very few tumors of these sites were seen in rats treated with 2,6-dimethyl- or 2,2,6,6-tetramethyl-nitrosopiperidine. It was concluded that blockage by methyl groups of one or more carbon atoms alpha to the nitroso function in nitrosopiperidine significantly reduces carcinogenic activity of the molecule.     

Fluoro-substituted N-nitrosamines. 5. Carcinogenicity of N-nitroso-bis-(4,4,4-trifluoro-n-butyl)amine in rats

N-Nitroso-bis-(4,4,4-trifluoro-n-butyl)amine (F-6-NDBA) hasbeen synthesized as a derivative of the rat urinary bladdercarcinogen N-nitrosodibutylamine (NDBA). Its chronic administrationby gavage to Sprague-Dawley rats induced a significant incidenceof malignant tumors of the liver and the lungs. Tumors in theliver were diagnosed as multifocal hepatocelluar carcinomasand those of the lungs were mainly squamous cell carcinomas.No tumors were observed in the urinary bladder. This confirmsearlier results from metabolism and animal carcinogenicity experimentsindicating the importance of metabolic oxidation at the terminalcarbon atom of NDBA for its organ-specific effects. This metabolic-oxidation is blocked in F-6-NDBA.