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The nucleotide-permeable escherichia coli cell, a sensitive DNA repair indicator for carcinogens, mutagens, and antitumor agents binding covalently to DNA

Die nukleotid-permeable Escherichia coli-Zelle, ein empfindlicher DNA Reparaturindikator für kovalent an DNA bindende Carcinogene, Mutagene und antineoplastische Substanzen

Zeitschrift für Krebsforschung und Klinische Onkologie volume 92, pages 177–214 (1978)Cite this article

Summary

Ether-permeabilized (nucleotide-permeable) Escherichia coli cells respond to alkylating and arylalkylating carcinogens with DNA excision repair, as assessed by their stimulation of DNA repair synthesis. In the present work, we have investigated whether DNA repair synthesis in ether-treated E. coli cells can serve as a general indicator to monitor the DNA-binding of carcinogens, mutagens and antitumor agents. Therefore, a standard assay was developed and comparative analyses were performed on 11 ultimate carcinogens, 10 proximate carcinogens, 2 tumor promoters, 6 mutagens, and 12 antitumor agents.

All ultimate carcinogens (alkylating, acylating, arylalkylating agents) and mutagens (e.g., hydrogen peroxide, acridine derivatives) caused DNA excision repair in wild type cells as measured by [3H] dTMP incorporation and simultaneously inhibited replicative DNA synthesis to various extents. Control experiments with the mutant cells uvrA and uvrB were performed to determine whether the pyrimidine-dimer-specific UV-endonuclease was involved in the removal of DNA damage. This was found to be true for the ultimate carcinogens (Ac)2ONFln, mitomycin C, and for very reactive alkylating carcinogens. None of the ultimate carcinogens induced repair polymerization in mutant cells lacking the 5′-3′ exonucleolytic activity of DNA polymerase I.

Proximate carcinogens, such as Me2NNO, 4-nitroquinoline-1-oxide and aflatoxins, did not induce excision repair in the standard assay, probably because of the inability of E. coli to perform the activation steps necessary for covalent DNA-binding. However, Me2NNO, when pretreated with Udenfriend's hydroxylating mixture, gave rise to a low level of repair polymerization in ethertreated cells.

Intercalating mutagens, such as quinacrine and ethidum bromide, inhibited replicative DNA synthesis. However, they were not found to be repair-inducers.

The tumor promoters TPA and phorbol-12,13-didecanoate did not cause excision repair, even when applied at high concentrations, nor did they inhibit repair synthesis stimulated by MeNOUr or (Ac)2ONFln.

The antitumor agents may be classified into two groups on the basis of the influence they exert on DNA synthesis: members of the first group (involving BCNU and bleomycin) stimulate repair polymerization and, in addition, inhibit DNA replication. These compounds are known to bind covalently to DNA. The second group of drugs (including adriamycin and cis-Pt(II)diammine complexes) inhibits DNA replication without stimulating repair synthesis. The predominant DNA-interaction of these compounds is known to be a non-covalent (i.e., intercalative, electrostatic) binding.

Our experiments show that the ether-permeabilized E. coli cell can be successfully used to test ultimate carcinogens, mutagens and antitumor agents for repair-inducing and replication-inhibiting activity. The standard test might be extended to pre- and proximate carcinogens, provided these can be suitably activated.

Zusammenfassung

Äther-permeabilisierte (nukleotid-permeable) Escherichia coli-Zellen sprechen auf alkylierende und arylalkylierende Carcinogene mit DNA Exzisionsreparatur an. Der Grad der Stimulation der DNA-Reparatursynthese kann quantitativ erfaßt werden. In der vorliegenden Arbeit wurde untersucht, ob die Äther-behandelte E. coli-Zelle ein allgemein anwendbares Reparaturindikator-System darstellt, das die Bindung von Carcinogenen, Mutagenen und antineoplastischen Substanzen an DNA anzeigt. Aus diesem Grund wurde ein Standardtest entwickelt, mit dem wir 11 direkte Carcinogene, 10 indirekte Carcinogene, 2 Tumorpromotoren, 6 Mutagene und 12 antineoplastische Verbindungen vergleichend prüften.

Gemessen an der Stimulation der DNA Reparatur, verursachten alle direkt an DNA wirkenden Carcinogene (alkylierende, acylierende, arylalkylierende Verbindungen) und Mutagene (z. B. Wasserstoffperoxid, Acridin-Derivate) DNA Exzisionsreparatur in Wildtypzellen und hemmten gleichzeitig, in unterschiedlichem Maße, die replikative DNA Synthese. In Vergleichsexperimenten mit den Defektmutanten uvrA und uvrB wurde geprüft, ob die Pyrimidin-Dimeren-spezifische UV-Endonuklease an der Entfernung der DNA Schäden beteiligt war. Dies war bei einer Reihe von direkt wirkenden Carcinogenen [(Ac)2ONFln, Mitomycin C, sowie sehr reaktiven alkylierenden Carcinogenen] der Fall.

Keines der direkt wirkenden Carcinogene stimulierte Reparaturpolymerisation in einer Defektmutante, der die 5′-3′ exonukleolytische Aktivität der DNA Polymerase I fehlte.

Indirekt wirkende Carcinogene (wie Me2NNO, 4-Nitrochinolin-1-oxid, Aflatoxine) riefen im Standardtest keine Exzisionsreparatur hervor; der wahrscheinliche Grund ist, daß E. coli die für kovalente DNA-Bindung erforderlichen Aktivierungsschritte nicht ausführen kann. Wurde jedoch Me NNO mit Udenfriend's Hydroxylierungsreagenz vorbehandelt, so löste es in Äther-permeabilisierten Zellen ein geringes Maß an Reparaturpolymerisation aus.

Interkalierende Mutagene (wie Atebrin, Äthidiumbromid) hemmten zwar die replikative DNA Synthese; sie stimulierten jedoch nicht die Exzisionsreparatur.

Die Tumor promotoren TPA und Phorbol-12,13-didekanoat zeigten selbst bei hohen Konzentrationen keine reparaturinduzierende Wirkung. Ebensowenig vermochten diese Verbindungen die durch MeNOUr oder (Ac)2ONFln ausgelöste Reparatursynthese zu hemmen.

Die untersuchten antineoplastischen Verbindungen lassen sich nach ihrem Einfluß auf die DNA Synthese in zwei Gruppen einteilen: Die eine Gruppe umfaßt Verbindungen wie BCNU und Bleomycin, die die Reparaturpolymerisation stimulieren und-zusätzlich — die DNA Replikation hemmen. Von den Substanzen dieser Gruppe ist bekannt, daß sie kovalent an DNA binden. Die zweite Gruppe umfaßt Verbindungen wie Adriamycin und die cis-Pt(II)diamminkomplexe, die die DNA Replikation hemmen, ohne die Reparatursynthese zu stimulieren. Von diesen Substanzen ist bekannt, daß ihre DNA-Wechselwirkungen überwiegend nicht-kovalenter (d.h. interkalierender, elektrostatischer) Natur sind.

Unsere Experimente zeigen, daß die Äther-permeabilisierte E. coli-Zelle mit Erfolg eingesetzt werden kann, um direkt auf DNA wirkende Carcinogene, Mutagene und antineoplastische Substanzen bezüglich ihrer reparaturinduzierenden und replikationshemmenden Eigenschaften zu prüfen. Der Standardtest läßt sich auch auf indirekt Carcinogene ausdehnen, vorausgesetzt, daß eine ausreichende Aktivierung erzielt werden kann.

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Abbreviations

EGTA:

ethyleneglycol-bis-(2-aminoethyl)-N,N′-tetraacetic acid

butyl-PBD:

2-(4-t-butylphenyl)-5-(4-biphenylyl)-1,2,3-oxadiazole

Me2SO:

dimethyl sulfoxide

MeNOUr:

N-methyl-N-nitrosourea

EtNOUr:

N-ethyl-N-nitrosourea

Me(NO)(NO2)Gdn:

N-methyl-N′-nitro-N-nitrosoguanidine

Me2NNO:

dimethyl nitrosamine

(Ac)2ONFln:

N-acetoxy-2-acetylaminofluorene

(Ac)NOHFln:

N-hydroxy-2-acetylaminofluorene

(Ac)NHFln:

2-acetylaminofluorene

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

BCNU:

N,N′-bis(2-chloroethyl)-N-nitrosourea

CCNU:

N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea

H 33258:

(“Hoechst 33258”), 2,2(4-hydroxyphenyl)-6-benzimidazolyl-6-(1-methyl-4-piperazyl)-benzimidazol-trihydrochloride

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  1. Deutsches Krebsforschungszentrum, Institut für Biochemie, Im Neuenheimer Feld 280, D-6900, Heidelberg, Germany

    H. W. Thielmann & H. Gersbach

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  1. H. W. Thielmann
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  2. H. Gersbach
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This work was supported by the Deutsche Forschungsgemeinschaft. The authors would like to acknowledge the excellent technical assistance of Miss. U. Reygers. We also thank Dr. A. Fried and Dr. G. Robert N. Jones for critically reading the manuscript and for helpful suggestions

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Thielmann, H.W., Gersbach, H. The nucleotide-permeable escherichia coli cell, a sensitive DNA repair indicator for carcinogens, mutagens, and antitumor agents binding covalently to DNA. Z. Krebsforsch. 92, 177–214 (1978). https://doi.org/10.1007/BF00312409

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  • DOI: https://doi.org/10.1007/BF00312409

Key words

  • Carcinogens
  • Mutagens
  • Antitumor Agents
  • DNA Repair

Schlüsselwörter

  • Carcinogene
  • Mutagene
  • antineoplastische Substanzen
  • DNA Reparatur