Molecular Pharmacology, Vol 16, 287-296, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

The Mechanism of Inhibition of DNA Transcription In Vitro by Nitracrine (Ledakrin, C-283)

KRYSTYNA LASKA ¹, LESZEK SZMIGIERO ¹, BARBARA JAROS-KAMISKA ¹, EWA CIESIELSKA ¹, and MAREK GNIAZDOWSKI ¹

¹ Department of General Chemistry, Institute of Physiology and Biochemistry, Medical School, 90-131 Lód, Poland

In the presence of mercaptoethanol or dithiothreitol, an anticancer drug nitracrine (1-nitro-9,3-N,N-dimethylaminopropylaminoacridine, Ledakrin, C-283) forms irreversible complexes of decreased template activity with DNA. Up to 7 irreversibly bound [³H]-nitracrine molecules were found per 10⁴ nucleotides of calf thymus DNA in the presence of mercaptoethanol. Both average chain length and the number of polynucleotides decreased in the presence of the drug. It can be concluded that binding of the drug to DNA inhibits the initiation and elongation steps or induces a pre-early termination of RNA synthesis. On the other hand DNA bearing as much as 20 molecules of the drug per 10³ of nucleotides (the complex formed in the presence of dithiothreitol) retains its ability to bind E. coli RNA polymerase.

Note:
ACKNOWLEDGMENTS The authors are grateful to Miss Magorzata Affeltowicz, Mrs Grayna Obara and Mrs Krystyna Myszkowska for valuable technical assistance. We wish to thank Dr R. S. Hayward for his critical reading of the manuscript and helpful comments.