Resistance to adriamycin cytotoxicity among respiratory-deficient mutants in yeast

Abstract

Saccharomyces cell uptake of Adriamycin and the ensuing cytotoxic response were found to be dependent upon the ionic strength of the medium used for drug treatment. A given concentration of Adriamycin which inhibited growth in complete medium ws found to be significantly cytotoxic when administered in water. Many survivors after Adriamycin treatment in water were found to be respiratory-deficient petite mutants containing mitochondrial deoxyribonucleic acid mutations. Petite mutants arising after Adriamycin treatment were not induced but selected from the preexisting population of spontaneously derived petite mutants (normal frequency, 2%) due to an increased resistance of these mutants to killing by Adriamycin as compared with normal respiratory-sufficient cells. The responses to Adriamycin in mitochondrial deoxyribonucleic acid respiratory-deficient mutants (rho-, rho degrees, mit-) with different impaired mitochondrial functions was studied. All were similarly more resistant to killing by Adriamycin than wild-type cells. The common deficiency shared by these mutants, i.e., nonfunctioning electron transport, may play a role in protecting these mutants from Adriamycin cytotoxicity. In addition, normal cells grown on glycerol, requiring aerobic respiration for carbon source utilization were more susceptible to killing by Adriamycin than cells grown on glucose. These studies suggest that a mitochndrial function in yeast may interact with Adriamycin to potentiate a cell cytotoxic mechanism of the drug.