Selective Loss of Mitochondrial DNA after Treatment of Cells

Ditercalinium (NSC 335153), a bifunctional intercalating molecule with antitumor activity, is found to express its toxicity through a mech anism of action completely different from that of other monointercalating agents. Electron microscopic observation of ditercalinium-treated cells shows a drastic alteration of mitochondria! structure. Cells deficient in mito chondria! respiration (GSK3 cells) isolated by A. Franchi et al. (Int. J. Cancer, 27: 819-827, 1981) are about 25-fold more resistant than cells deficient in glycolysis (DS7 cells) isolated by J. Pouysségur et al. (Proc. Nati. Acad. Sci. USA, 77: 2698-2701, 1980). Revenants have been isolated from GSK3 cells. In these cells, the sensitivity to ditercalinium has been recovered with mitochondria! respiration. Ditercalinium treat ment of 1.1210 leukemic mouse cells leads to a specific elimination of mitochondria! DNA detected by DNA-DNA hybridization. No measur able alteration of nuclear DNA is observed. In contrast, the monomeric analogue of ditercalinium only alters nuclear DNA and does not change the mitochondria! DNA content. The activity of cytochrome c oxidase, an enzyme which contains a subunit coded by the mitochondria! DNA, decreases exponentially in treated cells with a half-life of 24 h, corre sponding to the turnover of the enzyme. These results suggest that ditercalinium exerts a specific cytotoxic effect at the level of mitochondria! DNA. This action could account for the delayed cytotoxicity induced by this compound.