Differential Metabolic Responses of Susceptible and Resistant Mouse Leukemia Cells to 8-Azaguanine2

Abstract

Leukemia cells susceptible and resistant to 8-azaguanine have been studied with regard to direct metabolic changes in respiration and glycolysis produced by this drug. 8-Azaguanine caused a prompt and marked increase in glycolysis in vitro of susceptible cells but not of resistant cells, with concentrations of drug that ranged from about one-fourth to four times the pharmacologic level commonly employed (50 mg./kg.). Respiratory inhibition was observed in both types of cells, but at lower doses in the susceptible cells than in the resistant line. The increase in glycolysis and decrease in respiration were also observed in vitro following a single subcutaneous dose of 8-azaguanine given to mice bearing the susceptible cells. These metabolic effects observed in vitro tended to disappear after repeated daily exposure of the cells to the drug in vivo, and did so within a transplant generation. The significance of these findings is discussed in relation to a rationale of chemotherapy based on well-established metabolic properties characteristic of all cancer cells.