IN-VITRO SELECTION OF HALOFANTRINE RESISTANCE IN PLASMODIUM-FALCIPARUM IS NOT ASSOCIATED WITH INCREASED EXPRESSION OF PGH1

Recent investigations into quinoline and phenanthrene methanol resista nce in Plasmodium falciparum have described a linkage between amplific ation of the mdr homologue pfmdr1 and decreased susceptibility to mefl oquine (MQ) and halofantrine (HF). We have examined the current theori es on cross-resistance patterns and pfmdr1 gene expression by comparin g the chloroquine (CQ) resistant isolate K1 with K1Hf, developed from the K1 isolate by intermittent exposure to halofantrine. Reduced halof antrine susceptibility in K1Hf was accompanied by reduced sensitivity to mefloquine and increased sensitivity to chloroquine. These sensitiv ity changes were reflected by changes in parasite drug accumulation. T he loss of high level chloroquine resistance in K1Hf was associated wi th an inability of verapamil to enhance chloroquine sensitivity or acc umulation. In contrast verapamil retained the chemosensitising potenti al against quinine in this isolate. The changes in phenotype were achi eved without any amplification or increased expression of pfmdr1 or re version of the Tyr(86) mutation in the gene. Our data indicates that a cquisition of halofantrine and mefloquine resistance and the loss of h igh level chloroquine resistance can be achieved without enhanced expr ession of the pfmdr1 gene product. Copyright (C) 1996 Elsevier Science B.V.