A COMPARISON OF THE PHENOMENOLOGY AND GENETICS OF MULTIDRUG-RESISTANCE IN CANCER-CELLS AND QUINOLINE RESISTANCE IN PLASMODIUM-FALCIPARUM

Plasmodium falciparum is the causative agent of the most deadly form o f human malaria. Chemotherapy traditionally has been the main line of defence against this parasite, and chloroquine, the drug of choice, ha s been one of the most successful drugs ever developed. Unfortunately, the evolution and spread of resistance to chloroquine and other quino line containing drugs means that these compounds are now virtually use less in many endemic areas. Future prospects for the use of quinoline compounds improved considerably when it was demonstrated that chloroqu ine resistance could be circumvented in vitro by a number of structura lly and functionally unrelated compounds such as verapamil and desipra mine. The phenomenon of resistance reversal by compounds such as verap amil is also a key feature of drug resistance in mammalian cells, and this has raised the possibility that the underlying mechanisms of drug resistance of the two cell types could be similar. This hypothesis ha s prompted a large number of studies into the genetics and biochemistr y of resistance to quinoline-containing drugs in P. falciparum. Both t he genetic and the biochemical studies have raised issues of controver sy and stimulated much debate. These issues are discussed in this revi ew, in the context of a comparison with the genetics and biochemistry of multidrug resistance in mammalian cells. (C) 1998 Elsevier Science Inc.