Selective loss of mitochondrial DNA after treatment of cells with ditercalinium (NSC 335153), an antitumor bis-intercalating agent.
Ditercalinium (NSC 335153), a bifunctional intercalating molecule with antitumor activity, is found to express its toxicity through a mechanism of action completely different from that of other monointercalating agents. Electron microscopic observation of ditercalinium-treated cells shows a drastic alteration of mitochondrial structure. Cells deficient in mitochondrial 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. Natl. Acad. Sci. USA, 77: 2698-2701, 1980). Revertants have been isolated from GSK3 cells. In these cells, the sensitivity to ditercalinium has been recovered with mitochondrial respiration. Ditercalinium treatment of L1210 leukemic mouse cells leads to a specific elimination of mitochondrial DNA detected by DNA-DNA hybridization. No measurable alteration of nuclear DNA is observed. In contrast, the monomeric analogue of ditercalinium only alters nuclear DNA and does not change the mitochondrial DNA content. The activity of cytochrome c oxidase, an enzyme which contains a subunit coded by the mitochondrial DNA, decreases exponentially in treated cells with a half-life of 24 h, corresponding to the turnover of the enzyme. These results suggest that ditercalinium exerts a specific cytotoxic effect at the level of mitochondrial DNA. This action could account for the delayed cytotoxicity induced by this compound.
Segal-Bendirdjian
E
E
Unité de Physicochimie Macromoléculaire (CNRS UA 147, INSERM U 140), Institut Gustave Roussy, Villejuif, France.
Coulaud
D
D
Roques
B P
BP
Le Pecq
J B
JB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000032:analysis; D006019:Glycolysis / Q000187:drug effects; D007364:Intercalating Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000648:ultrastructure
D000970:Antineoplastic Agents; D002227:Carbazoles; D004272:DNA, Mitochondrial; D007364:Intercalating Agents; D003576:Electron Transport Complex IV; C042804:ditercalinium