Druckrey, H; Preussmann, R; Ivankovic, S; Schmähl, D
All symmetrically substituted dialkylnitrosamines produced carcinomas of the liver. The only exception was di-n-butylnitrosamine, which also lead to carcinomas of the urinary bladder. Subcutaneous injection of this compound produced only bladder tumors. Diamylnitrosamine on subcutaneous application, however, selectively produced lung cancer. Diallyl-, dicyclohexyl-, di-phenyl- and dibenzylnitrosamine were non-carcinogenic. Non-symmetrical dialkylnitrosamines, especially methylnitrosamines with either the amyl-, cyclohexyl-, phenyl-, benzyl- or phenylethyl-group as the 2nd substituent and also bis-(methyl-nitroso)-ethylendiamine, ethyl-vinyl- and ethyl-n-butyl-nitrosamine selectively produced carcinomas of the esophagus; these tumors were also observed after parenteral application. Methyl-allyl-nitrosamine induced malignant tumors of the kidney, especially after intravenous injection. In the group of cyclic nitrosamines, N-nitroso-pyrrolidine, -morpholine,and N-Nitroso-N[image]-carbethoxypiperazine induced cancer of the liver. Nitrosopiperidine and dinitrosopiperazine produced carcinomas of the esophagus after oral as well as after intravenous application. After subcutaneous injection, however, tumors of the nasal cavity (ethmoturbinalia) were observed, mostly esthesio-neuro-epitheliomas of the olfactory nerve. Nitrosamines with functional groups also produced malignant tumors in different organs. Ethyl-ethanol- and diethanol-nitrosamine as well as its ethylester in acute experiments proved to be non-toxic, but regularly produced liver cancer after continuous treatment. Butyl-butanol-(4)-nitrosamine selectively induced carcinomas of the urinary bladder. Esophageal carcinomas were obtained with methyl-nitrosamino-sulpholane, nitroso-sarkosine, its ethylester and N-nitrosopicolyl (4)-ethylamine; with the latter compound also after intravenous injection. Several acyl-alkyl-nitrosamides, yielding diazoalkanes on heterolytic decomposition, as well as diazoacetic-acid-ethylester produced carcinomas of the forestomach on oral application. Subcutaneous injection of several nitrosamides gave rise to local sarcomas at the site of injection. When given intravenously, memylnitroso-urethane selectively produced lung cancer; several me thylnitroso-ureas induced malignant tumors in the brain, spinal cord, and/or peripheral nervous system. These tumors could be induced regularly for the 1st time as a systemic effect. Diazoacetic-acid-ethylester after intravenous injection produced skin cancer in rats. The biochemical mechanism of action is discussed on the basis of the results described. The "diazoalkane-theory" for the carcinogenic action of N-nitroso-compounds is confirmed. Dialkylnitrosamines on subcutaneous injection produced cancer only in remote organs. The selective production of cancer in many organs shows that the activation is not restricted to the liver. Therefore, the 1st step in activation is presumed to be an enzymatic [alpha]-hydroxylation. Since all following reactions to the final stage of the alkylating diazoalkane occur "spontaneously", the initial [alpha]-hydroxylation is considered as the reason for the remarkable organotropic effects observed. The quantitative analysis of the dose-response-relationships resulted in normal distributions over the total dose administered as well as over the individual induction time in all cases. Tumors occurring in different organs clearly fell into the same normal distribution. The injection of small and otherwise subthreshold doses of ethyl-nitroso-urea to pregnant rats lead to the result that practically all offspring died with malignant tumors of the brain, the spinal cord and/or the peripheral nervous system. During fetal development the sensitivity was at least 10-fold higher than in adults, most probably due to the greater activity of nucleic acids as target of the primary carcinogenic action. The results described present new and serious aspects to the problem of the causation of cancer and underline the necessity of preventive measures.