Abstract
Summary
The cytotoxicity of hadacidin in KB cell cultures was found to be potentiated by phenethylbiguanide as has been observed previously with known inhibitors of glycolysis. Glucose utilization and lactic acid production were inhibited in proportion to the cytotoxicity. The effects of hadacidin were antagonized by pyruvate, α-ketobutyrate, oxalacetate, and L-aspartate, but not by asparagine or pyrimidines. A variety of other metabolites, notably those in the Krebs tricarboxylic cycle, possessed some activity. Alpha-ketobutyrate and aspartate were additive in their capacity to overcome the cytotoxicity of hadacidin. Adenine at low concentrations effectively antagonized the cytotoxicity of hadacidin while adenosine, inosine, and hypoxanthine were ineffective.
The data support interference with purine metabolism as a mechanism for cytotoxicity of hadacidin in tissue culture. In addition, interference with energy metabolism appears likely.
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