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Untersuchungen zur Organotropie der alkylierenden Wirkung von Dimethylnitrosamin (DMNA) und Nitrosomethylharnstoff (NMH) in vivo

Investigations of the organotropy of alkylating activity of dimethyl-nitrosamine (DMNA) and nitroso-methyl-urea (NMH) in vivo

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Summary

  1. 1.

    The alkylating action and the tumor inhibition of 14C-dimethylnitrosamine and 14C-methylnitrosourea was investigated on transplanted tumors in rats and mice. After intravenous application of 14C-dimethylnitrosamine no formation of 7-methylguanine in the RNA of the tumor could be detected, but was found after application of NMH. These observations correspond to the chemotherapeutic action of methylnitrosourea on the reticulum cell sarcoma of the mouse, whereas dimethylnitrosamine had no tumor-inhibiting action.

  2. 2.

    The biological incorporation of the 14C-activity into the purine bases of the tumor-RNA after application of both compounds could no longer be observed in hepatectomized rats. After application of 14C-dimethylnitrosamine the tumor-RNA was not labelled, whereas the labelling after application of 14C-methylnitrosourea was only due to the formation of 7-14C-methylguanine.

  3. 3.

    After application of 14c-NMH the eluation pattern of RNA hydrolysates from muscle and liver of rainbow trout resembled that of RNA of transplanted tumors of hepatectomized rats after application of the same compound.

  4. 4.

    The intermediate formation of a methylnitrosocarbamic acid as a common stage in the formation of the methyl-cation from methylnitrosourea and dimethylnitrosamine is assumed by different pathways. This explains the different organotropic action in alkylation of both compounds.

  5. 5.

    The metabolic formation of formaldehyde can be explained by the oxydation of primary formed methanole, which is produced by the reaction of the methyl-cation with OH-groups of water.

Zusammenfassung

  1. 1.

    An Transplatationstumoren von Ratten und Mäusen wurde die alkylierende und tumorhemmende Wirkung von 14C-Dimethylnitrosamin und 14C-Methylnitrosoharnstoff untersucht. Nach intravenöser Applikation von 14C-Dimethylnitrosamin war keine Bildung von 7-Methylguanin in der Ribonucleinsäure des Tumors nachweisbar. Hingegen kam es nach intravenöser Gabe von 14C-Methylnitrosoharnstoff zu einer gut nachweisbaren Methylierung des Guanins der Tumor-RNS. In Korrelation zu diesen Beobachtungen steht der chemotherapeutische Effekt von Methylnitrosoharnstoff, während Dimethylnitrosamin keine tumorhemmende Wirkung besaß.

  2. 2.

    Die nach Applikation beider Verbindungen beobachtete biologische Inkorporation der 14C-Aktivität in die Purinbasen der Tumor-RNS konnte bei hepatektomierten Ratten nicht mehr beobachtet werden.

  3. 3.

    Untersuchungen der Ribonucleinsäuren aus Leber und Muskulatur von Regenbogenforellen nach Gabe von 14C-Methylnitrosoharnstoff führten zu ähnlichen Ergebnsisen, wie sie bei der Analyse der Tumor-Ribonucleinsäuren hepatektomierter Ratten nach Applikation der gleichen Verbindung beobachtet wurden.

  4. 4.

    Es wird für die Bildung des Methylcations aus Methylnitrosoharnstoff und Dimethylnitrosamin als gemeinsame Zwischenstufe die intermediäre Bildung einer Methylnitrosocarbaminsäure angenommen, die auf verschiedenen Reaktionswegen aus DMNA und NMH entsteht. Dies läßt eine Deutung der unterschiedlichen Organotropie der Alkylierung beider Verbindungen zu.

  5. 5.

    Die metabolische Bildung von Formaldehyd läßt sich durch die Oxydation des primär gebildeten Methylalkohols erklären, welcher durch Reaktion des Methylcations mit den OH-Gruppen des Wassers entsteht.

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Authors and Affiliations

  1. Institut für exp. Toxikologie und Chemotherapie am Deutschen Krebsforschungszentrum Heidelberg, Heidelberg, Deutschland

    F. W. Krüger, H. Osswald, G. Walker & E. Schelten

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  1. F. W. Krüger
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  2. H. Osswald
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  3. G. Walker
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  4. E. Schelten
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Herrn Prof. Dr. Dr. h. c. K. H. Bauer zum 80. Geburtstag gewidmet.

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Krüger, F.W., Osswald, H., Walker, G. et al. Untersuchungen zur Organotropie der alkylierenden Wirkung von Dimethylnitrosamin (DMNA) und Nitrosomethylharnstoff (NMH) in vivo. Z Krebs-forsch 74, 434–447 (1970). https://doi.org/10.1007/BF00531225

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