Multidrug Resistance-Associated Proteins

Publication Title: 
Biological & Pharmaceutical Bulletin

Overcoming MDR (multidrug resistance) phenomena is a crucial aspect of cancer chemotherapy research. Artemisinin and its derivatives have been found to inhibit the proliferation of cancer cells in the microM range. They poorly inhibited the function of P-glycoprotein and did not inhibit the function of MRP1-protein. The concentrations required to inhibit by 50% the function of P-glycoprotein are 110+/-5 microM.

Author(s): 
Reungpatthanaphong, Paiboon
Mankhetkorn, Samlee
Publication Title: 
Trends in Pharmacological Sciences

The ability to treat and control Plasmodium falciparum infection through chemotherapy has been compromised by the advent and spread of resistance to antimalarial drugs. Research in this area has identified the P. falciparum chloroquine resistance transporter (PfCRT) and the multidrug resistance-1 (PfMDR1) transporter as key determinants of decreased in vitro susceptibility to several principal antimalarial drugs.

Author(s): 
Valderramos, Stephanie G.
Fidock, David A.
Publication Title: 
The Journal of Antimicrobial Chemotherapy

BACKGROUND AND OBJECTIVES: The immunosuppressant cyclosporin A and a number of other cyclosporins have potent and selective antimalarial activity. Their exact mechanism of antimalarial action is unknown but the structure-activity relationships for malarial parasite inhibition and immunosuppression differ markedly. The 3'-keto derivative of cyclosporin D (valspodar) is particularly potent against the human malarial parasite Plasmodium falciparum in culture but causes negligible immunosuppression.

Author(s): 
Gavigan, C. S.
Shen, M.
Machado, S. G.
Bell, A.
Publication Title: 
Nucleic Acids Symposium Series (2004)

We studied DNA sequence polymorphism, expression level of pfmdr1 gene and sensitivity of major antimalarial drugs in both mefloquine sensitive and resistant strains to elucidate mechanism of mefloquine resistance. Mefloquine-resistant 523a R/24 strain exhibited decreased susceptibility to mefloquine, artemisinin and halofantrine whereas increased susceptibility to chloroquine. We found a novel point mutation in pfmdr1 gene of 523a R/24 strain. Moreover, overexpression of mRNA of pfmdr1 has been observed in this strain.

Author(s): 
Nishiyama, Yuko
Okuda, Yohei
Kim, Hye-Sook
Huruta, Takahisa
Kimura, Mikio
Wataya, Yusuke
Publication Title: 
The Journal of Infectious Diseases

BACKGROUND: Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. METHODS: In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. RESULTS: Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections.

Author(s): 
Uhlemann, Anne-Catrin
McGready, Rose
Ashley, Elizabeth A.
Brockman, Alan
Singhasivanon, Pratap
Krishna, Sanjeev
White, Nicholas J.
Nosten, François
Price, Ric N.
Publication Title: 
Tropical medicine & international health: TM & IH

OBJECTIVES: Many countries are now adopting artemisinin-based combination therapy (ACT) for treatment of Plasmodium falciparum malaria. In multi-drug resistant areas in South East Asia amplifications of the pfmdr1 gene are frequent and tentatively associated with reduced susceptibility to the common quinoline partner drugs mefloquine and lumefantrine. In Africa where amodiaquine is one of the favoured quinoline partner drugs in ACT, studies on multi-drug resistance associated pfmdr1 gene amplifications are urgent.

Author(s): 
Holmgren, Gabrielle
Björkman, Anders
Gil, José Pedro
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

Artemisinin combination therapies (ACTs) have recently been adopted as first-line therapy for Plasmodium falciparum infections in most malaria-endemic countries. In this study, we estimated the association between artesunate-mefloquine therapy failure and genetic changes in the putative transporter, pfmdr1. Blood samples were acquired from 80 patients enrolled in an 2004 in vivo efficacy study in Pailin, Cambodia, and genotyped for pfmdr1 copy number and haplotype.

Author(s): 
Alker, Alisa P.
Lim, Pharath
Sem, Rithy
Shah, Naman K.
Yi, Poravuth
Bouth, Denis Mey
Tsuyuoka, Reiko
Maguire, Jason D.
Fandeur, Thierry
Ariey, Frédéric
Wongsrichanalai, Chansuda
Meshnick, Steven R.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

We measured in vitro antimalarial drug susceptibility of 84 Plasmodium falciparum field isolates from Blantyre, Southern Malawi, using the WHO microtest and the lactate dehydrogenase assay. We also genotyped these isolates to investigate whether variation in their absolute drug sensitivity is associated with specific sets of pfcrt and pfmdr-1 mutations harbored by parasites.

Author(s): 
Nkhoma, Standwell
Molyneux, Malcolm
Ward, Stephen
Publication Title: 
Antimicrobial Agents and Chemotherapy

Key parasite polymorphisms were assessed in subjects treated for malaria with artesunate-amodiaquine in Tororo, Uganda. For pfcrt, all of the isolates tested had the CVIET haplotype. For pfmdr1, 86Y and 1246Y were common at baseline and their prevalences were significantly higher in new isolates after therapy, indicating that treatment selected for mutations associated with a decreased response to amodiaquine.

Author(s): 
Nsobya, Samuel L.
Dokomajilar, Christian
Joloba, Moses
Dorsey, Grant
Rosenthal, Philip J.
Publication Title: 
Tropical medicine & international health: TM & IH

OBJECTIVE: To evaluate the in vitro efficacy of artesunate (ATN) and artemether (ATH) against Plasmodium falciparum isolates from the Brazilian Amazon state of Pará and to search for mutations and/or altered copy numbers in the putative resistance-associated pfcrt, pfmdr1 and pfATPase6 genes. METHODS: In vitro efficacy of ATN and ATH was successfully measured in 56 freshly collected P. falciparum isolates, using a conventional WHO microtest with minor modifications. Single nucleotide polymorphisms (SNPs) in the same isolates were inspected using DNA sequencing and/or PCR-RFLP.

Author(s): 
Ferreira, Isabel D.
Martinelli, Axel
Rodrigues, Louise A.
do Carmo, Ediclei L.
do Rosario, Virgilio E.
Póvoa, Marinete M.
Cravo, Pedro

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