TOPOISOMERASE-II INHIBITORS INDUCE CLEAVAGE OF NUCLEAR AND 35-KB PLASTID DNAS IN THE MALARIAL PARASITE PLASMODIUM-FALCIPARUM

The topoisomerase II-specific inhibitors VP-16 and ciprofloxacin were used to investigate the presence of topoisomerase II activities associ ated with nuclear and 35-kb plastid DNAs of the malarial parasite Plas modium falciparum. The eukaryotic topoisomerase II inhibitor VP-16 ind uced cleavage of both nuclear and 35-kb parasite DNAs, In contrast, ci profloxacin, a fluoroquinolone drug known to act on the bacterial type II topoisomerase DNA gyrase, only induced cleavage of the Plasmodial 35-kb DNA, Drug-induced cleavage resulted in the protection of the 5'- but not 3'-ends of the cleaved nuclear and 35-kb DNAs from exonucleas e digestion, suggesting that the 5'-ends of the broken DNA were protei n-linked, a property reminiscent of DNA cleavage mediated by topoisome rase II enzymes, Furthermore, DNA cleavage induced by both VP-16 and c iprofloxacin was heat-reversible. This is the first evidence that P. f alciparum contains two distinct topoisomerase II activities that are m olecular targets for chemotherapeutic agents.