CLEAVABLE COMPLEX-FORMATION IN LEISHMANIA-CHAGASI TREATED WITH ANILINOACRIDINES

Anilinoacridines have recently been found to possess antiparasitic act ivity toward Leishmania, Trypanosoma, and Plasmodium species. These co mpounds have been examined for their ability to generate cleavable com plex, the protein-associated DNA lesion characteristic of topoisomeras e II involvement, in intact L. chagasi promastigotes. At cytotoxic con centrations, anilinoacridine compounds give cleavable complex in a who le cell assay which suggests that the drugs affect a nuclear topoisome rase II in the parasite. Linearization of kinetoplast DNA minicircles also occurs in parasites treated with anilinoacridines at similar conc entrations. Exonuclease digestions reveal that the linearized minicirc les are blocked at the 5' end but not at the 3' end, further implicati ng a kinetoplast topoisomerase II in the cleavage process. Interesting ly, cytotoxic alkylaminoacridines did not stimulate the production of cleaved DNA in the same experiments. DNA binding experiments showed no apparent correlation between the affinity of the compounds for DNA an d antileishmanial activity. Although multiple cytotoxic mechanisms are likely at work, these experiments suggest that topoisomerase II enzym e(s) are affected by antileishmanial anilinoacridines.