Plasmodium falciparum resistance to cytocidal versus cytostatic effects of chloroquine

With one exception (Gligorijevic et al., Mol Biochem Parasitol 2008;159:7–23.) all previous quantification of chloroquine (CQ) potency vs. P. falciparum has been by growth inhibition assays, meaning potency is defined as cytostatic potential and quantified by IC50 values. In this study we investigate the cytocidal potency of CQ and other common quinoline antimalarial drugs (quantified as LD50). Similar to results from assays for cytostatic potency, we are able to readily distinguish drug resistant from drug sensitive P. falciparum parasites as well as different degrees of resistance. However, we find that fold-resistance to CQ and other quinoline drugs quantified via LD50 ratios differs quite dramatically from fold resistance calculated via IC50 ratios. Also, importantly, we find that verapamil chemoreversal of CQ resistance differs when quantified via cytocidal vs. cytostatic assays, as do patterns of “multidrug” resistance in well-known laboratory strains of P. falciparum. The results have important implications for development of new antimalarial drugs and for fully defining the genetic loci that confer clinically relevant antimalarial drug resistance phenomena.

Figure optionsDownload high-quality image (24 K)Download as PowerPoint slideHighlights
► The first fast inexpensive fluorescence-based assay for quantifying cytocidal effects of antimalarial drugs is presented. For the first time, CQR parasites are quantified for resistance to cytocidal effects of quinoline antimalarial drugs.
► Using the assay, LD50 are quantified vs. several drugs for CQS and CQR strains of malarial. Fold resistance computed by ratioing LD50 are much different from fold resistance calculated by ratioing IC50.
► Patterns of multidrug resistance for well-known laboratory CQR strains are found to be different when quantified via LD50 ratios, as compared to IC50 ratios.
► Verapamil is found to NOT reverse resistance to cytocidal effects of chloroquine, even though it has been known to reverse resistance to cytostatic effects for decades.