'Petite' mutagenesis by anticancer drugs in Saccharomyces cerevisiae

Abstract

The mitochondria of cancer cells are potential targets for chemotherapy. Drugs which primarily affect mitochondrial DNA can be screened using a 'petite' mutagenesis assay in Saccharomyces cerevisiae. We have used this approach to estimate the antimitochondrial effects of a range of current clinical and experimental antitumour drugs with varying modes of action. Of agents currently in the clinic, the antimetabolites 5-fluorouracil and methotrexate were extremely effective in inducing this respiratory defect, providing cells were growing during treatment. Adriamycin, BCNU, bleomycin, methyl CCNU, cis-platinum, chlorambucil, daunomycin, nitracine, nitrogen mustard and hycanthone were also weakly effective 'petite' mutagens, in either growing or non-growing conditions. None of the currently used agents but some experimental drugs induced high numbers of 'petite' mutants during growing or non-growing conditions. To date, where such agents have been tested clinically, they have proved either ineffective or very toxic. It is possible that antimitochondrial effects on non-proliferating cellular tissues such as the heart might cause unacceptable toxicity and preclude the clinical use of such agents. For those agents effective against proliferating cells, the mitochondria could be an important target for chemotherapy in some cell types. This type of drug appears relatively uncommon in the clinic at present. The 'petite' mutagenesis assay could be more widely used as a screen to optimize this property in development of analogues of current clinical agents, or in developing new types of anticancer drug.