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'Petite' mutagenesis by anticancer drugs in Saccharomyces cerevisiae
1Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
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.
Insights
Cancer drug screening identified antimitochondrial chemotherapy agents using a petite mutagenesis assay. Some clinical drugs showed effectiveness, while experimental ones were toxic, highlighting mitochondria as a potential cancer target.
Area of Science:
- Mitochondrial biology
- Cancer chemotherapy
- Drug screening
Background:
- Mitochondria are key targets for cancer chemotherapy.
- Antimitochondrial drugs can be screened using the petite mutagenesis assay in Saccharomyces cerevisiae.
Purpose of the Study:
- To evaluate the antimitochondrial effects of clinical and experimental anticancer drugs.
- To assess the utility of the petite mutagenesis assay for drug screening.
Main Methods:
- Utilized the petite mutagenesis assay in Saccharomyces cerevisiae.
- Screened a range of current clinical and experimental antitumour drugs.
- Assessed drug effects on mitochondrial DNA and respiratory function.
Main Results:
- 5-fluorouracil and methotrexate were highly effective antimitochondrial agents in growing cells.
- Several other clinical drugs showed weak antimitochondrial effects.
- Some experimental drugs induced high petite mutant numbers but proved toxic in clinical trials.
Conclusions:
- Mitochondria are a viable target for chemotherapy, particularly in proliferating cancer cells.
- The petite mutagenesis assay is a valuable tool for identifying and optimizing antimitochondrial anticancer drugs.
- Careful screening is needed to balance efficacy and toxicity, especially for non-proliferating tissues.