Disease relevance of PFMDR1

• Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance [1].
• The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties [2].
• The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant [3].
• Although long term studies of drug safety are not yet available, doxycycline and mefloquine appear to be the drugs of choice in areas where P. falciparum shows multidrug resistance [4].

High impact information on PFMDR1

• Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum [5].
• Resistance of Plasmodium falciparum to chloroquine shares features with the multidrug resistance (MDR) phenotype of mammalian tumor cells [5].
• In the 45 years since Burchenal's observation of chemotherapeutic drug resistance in tumor cells, many investigators have studied the molecular basis of tumor drug resistance and the phenomenon of tumor multidrug resistance (tumor MDR) [6].
• A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum [7].
• The nucleotide sequences of the possible genetic modulators of ART resistance (mdr1, cg10, tctp, and atp6) of sensitive and resistant parasites were compared [8].

Chemical compound and disease context of PFMDR1

• Multidrug resistance of Plasmodium falciparum is spreading throughout Africa. In Lambarene, Gabon where chloroquine-resistant malaria is prevalent, a randomized comparative trial with three regimens for treating P. falciparum malaria in adults was performed [9].

Biological context of PFMDR1

• These issues are discussed in this review, in the context of a comparison with the genetics and biochemistry of multidrug resistance in mammalian cells [7].
• Comparison of the alignments of both nucleotide and amino acid sequences of pvmdr1 with those of other Plasmodium multidrug-resistance genes revealed an open-reading frame of 4392 base pairs encoding a deduced protein of 1464 amino acids [10].
• We report here the identification of multiple 344-bp segments of amoeba DNA similar to the human multidrug resistance (mdr) gene using primers to conserved regions of the P-glycoprotein and the polymerase chain reaction (PCR) [11].
• At the nearest Thai site, Maesod, known for high-level multidrug resistance, the corresponding values for mefloquine IC50 and IC90 were 92 nM (95% CI, 71-121) and 172 nM (95% CI, 140-211) [12].
• Chloroquine resistance in Plasmodium chabaudi: are chloroquine-resistance transporter (crt) and multi-drug resistance (mdr1) orthologues involved [13]?

Associations of PFMDR1 with chemical compounds

• Concomitant with the increase in mefloquine resistance was a corresponding increase in the level of resistance to halofantrine and quinine, suggesting a true multidrug-resistance phenotype [14].
• However, given the history of the development of resistance to other antimalarial drugs, the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100% [15].
• Using direct sequencing of PCR products, we have analyzed sequence polymorphism of the dihydrofolate reductase-thymidylate synthase, dihydropteroate synthetase, and multidrug resistance 1 genes in a large number of clinical P. falciparum isolates collected in various areas of Cambodia [16].
• Furthermore, the expression of the mdr-like mRNAs was increased 3-4 times when clone C2 mutants were grown under drug pressure vs. the same parasites grown without emetine [11].
• It is postulated that these lipophilic drugs are interacting with the mechanism of resistance, possibly a multidrug resistance glycoprotein pump [17].

Analytical, diagnostic and therapeutic context of PFMDR1

• We assessed whether mutations in the Plasmodium falciparum multidrug-resistance gene 1 (pfmdr1) (C1034S, D1042N, and Y1246D) would predict treatment outcome during a 28-day in vivo treatment trial in the Peruvian Amazon [18].
• Molecular epidemiology of malaria in Yaoundé, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum [19].
• Three different antibodies were used to detect the malarial mdr 1 protein product by indirect immunofluorescence and/or immunoblot in fresh clinical isolates and clones of P. falciparum from different geographic origins [20].
• Multidrug resistance has rendered monotherapy for malaria useless in most parts of the world, and has also compromised the usefulness of many of the available combination chemotherapies [21].

References