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Abstract: The anti-malarial activity of the cancer chemotherapeutic agent cisplatin and cisplatin analogues was determined in Plasmodium falciparum. The cisplatin analogues included DNA-targeted acridine-tethered platinum compounds, carboplatin and transplatin. A [3H]-hypoxanthine incorporation assay was utilised to determine the IC50 of cisplatin and related analogues. The DNA-targeted Pt compounds and cisplatin were shown to have IC50 values that were less than 1μM in P. falciparum, with the acridine-tethered compounds having the greatest cytotoxicity. Carboplatin and transplatin had IC50 values of 12 and 16μM, respectively. The outcome for transplatin was particularly interesting since it is not cytotoxic in mammalian cells. These results were discussed with respect to the potential use of cisplatin and cisplatin analogues as anti-malarial agents. [Copyright &y& Elsevier]

Abstract: In this paper, we provided evidence that cisplatin is able to form adducts with cellular DNA in Plasmodium falciparum. The DNA sequence specificity of cisplatin adduct formation was determined in trophozoite-enriched P. falciparum cells and this paper represents the first occasion that the sequence specificity of cisplatin DNA damage has been observed in malaria cells. Utilising a sub-telomeric, 692bp repeat sequence in the P. falciparum genome, we were able to investigate the DNA adducts formed by cisplatin and five analogues. A run of eight consecutive guanines was the most prominent site of DNA damage in the malarial cells. This study suggests that the mechanism of P. falciparum cell death caused by cisplatin involves damage to DNA and hence inhibition of DNA replication and cell division. [Copyright &y& Elsevier]

The presence of adducts on the DNA double-helix can have major consequences for the efficient functioning of DNA repair enzymes. E. coli RecBCD (exonuclease V) is involved in recombinational repair of double-strand breaks that are caused by defective DNA replication, DNA damaging agents and other factors. The holoenzyme possesses a bipolar helicase activity which helps unwind DNA from both 3′- and 5′-directions and is coupled with a potent exonuclease activity that is also capable of digesting DNA from both 3′- and 5′-ends. In this study, DNA sequences were damaged with cisplatin or UV followed by RecBCD treatment. DNA damaging agents such as cisplatin and UV induce the formation of intrastrand adducts in the DNA template. It was demonstrated that RecBCD degradation was inhibited by either cisplatin-damaged or UV-damaged DNA sequences. This is the first occasion that RecBCD has been demonstrated to be inhibited by DNA adducts induced by cisplatin or UV. In addition, we quantified the amounts of DNA remaining after RecBCD treatment and observed that the level of inhibition was concentration and dose dependent. A DNA-targeted 9-aminoacridinecarboxamide cisplatin analogue was also found to inhibit RecBCD activity. [ABSTRACT FROM AUTHOR]