Inverse correlation between bacterial frameshift mutagenicity and yeast mitochondrial effects of antitumour anilinoacridines

Abstract

The mutagenicity of a series of derivatives of 9-anilinoacridine, including the clinical antitumour agent amsacrine, has been assessed using a bacterial frameshift tester strain ( Salmonella typhimurium TA1537) and a yeast petite colony assay ( Saccharomyces cerevisiae 5178B). The results have been compared with microbial mammalian cell cytotoxicity, DNA binding affinity and acridine base strength (pKa). Compounds containing strong electron donor substituents on the acridine ring, and which have a high acridine pKa, show minimal frameshift mutagenicity but are strong inducers of petite yeast mutants. Conversely, some compounds which have a high DNA binding constant but a significant proportion of uncharged form at neutral pH, show high frameshift mutagenicity but minimal induction of petite mutants. It is hypothesised that this inverse relationship arises from the presence of trans-membrane drug transport mechanisms which act to exclude some compounds, particularly strongly basic compounds from the cytoplasm and to concentrate them in mitochondria.