Plasmodium falciparum resistance to cytocidal versus cytostatic effects of chloroquine

Abstract

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 IC 50 values. In this study we investigate the cytocidal potency of CQ and other common quinoline antimalarial drugs (quantified as LD 50). 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 LD 50 ratios differs quite dramatically from fold resistance calculated via IC 50 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.