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6-Methylguanine and 6-methylguanosine inhibit colony-forming ability in a malignant xeroderma pigmentosum cell line but not in other xeroderma pigmentosum and normal human fibroblast strains after treatment with 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea

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  • Experimental Oncology
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Summary

The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G.

In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA.

HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.

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Abbreviations

XP:

xeroderma pigmentosum

HECNU:

1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea

HEPES:

N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

m6G:

6-methylguanosine

m6Gua:

6-methylguanine

he7G:

7-(2-hydroxyethyl)-guanosine

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Authors and Affiliations

  1. Institute of Biochemistry, Information and Statistics of the German Cancer Research Centre, Im Neuenheimer Feld 280, D-6900, Heidelberg, Federal Republic of Germany

    Heinz Walter Thielmann

  2. Institute of Documentation, Information and Statistics of the German Cancer Research Centre, Im Neuenheimer Feld 280, D-6900, Heidelberg, Federal Republic of Germany

    Lutz Edler

  3. Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, P.O. Box 3479, D-6750, Kaiserslautern, Federal Republic of Germany

    Norbert Müller & Gerhard Eisenbrand

Authors
  1. Heinz Walter Thielmann
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  2. Lutz Edler
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  3. Norbert Müller
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  4. Gerhard Eisenbrand
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Additional information

This work was supported by the Deutsche Forschungsgemeinschaft, SFB 136

The publication is dedicated to Professor E. Hecker on the occasion of his 60th birthday

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Thielmann, H.W., Edler, L., Müller, N. et al. 6-Methylguanine and 6-methylguanosine inhibit colony-forming ability in a malignant xeroderma pigmentosum cell line but not in other xeroderma pigmentosum and normal human fibroblast strains after treatment with 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea. J Cancer Res Clin Oncol 113, 67–72 (1987). https://doi.org/10.1007/BF00389969

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  • DOI: https://doi.org/10.1007/BF00389969

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