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Part-IIIAdvances Dihydropyridines and …also be their players in selected cases of MDR. These include ABCB4 (MDR3) andABCB11 (sister Pgp or BSEP), two proteins residing predominantly in the liver with afunction involved in the secretion of phosphatidyl choline and bile acids, respectively. 16-18MDR3 has been already shown to transport certain drugs as well. 19 In addition to MRP1,five homologues (MRP2-MRP6) have been cloned. Overexpression of MRP2 (an organicanion transporter which can also extrude hydrophobic compounds) was definitivelyshown to confer cancer MDR. 13,20 MRP3, an organic conjugate transporter, and MRP5, anucleoside transporter, are also candidate proteins for causing certain forms of drugresistance. 131.4.1 Basic Mechanism of MDR in CancerThe generally accepted mechanism of MDR is that the MDR proteins actively expel thecytotoxic drugs from tumor cells, maintaining the anticancer drug level below a cellkillingconcentration. Drug extrusion mediated by these primary active transporters isdriven by the energy of ATP hydrolysis. The most intriguing characteristic distinguishingthe MDR proteins from other mammalian transporters is their wide substrate specificity.Unlike other selective (classical) transport proteins, multidrug transporters have beenrecognized and handled as a wide range of substrates. This wide substrate specificityexplains the cross-resistance to several chemically unrelated compounds, thecharacteristic feature found in the MDR phenotype. 8-11Different tumors with MDR protein overexpression (e.g. hepatomas, lung or coloncarcinomas) often show primary (or intrinsic) resistance to cancer chemotherapy. Inaddition, cancer chemotherapy itself might induce the overexpression of these proteins, sothat the MDR clones become less sensitive to chemotherapy (secondary drug resistance).Treatment failure due to MDR is also found in connection with conditions other thancancer, including some autoimmune disorders and infectious diseases. 21-231.4.2 Nomenclature, Basic Structure and Membrane Topology of MDR ProteinsThe ABC superfamily is one of the largest families in proteins. The most recentannotation of the human genome sequence revealed 48 genes for ABC proteins. The ABCproteins were grouped into seven sub-classes, ranging from ABCA to ABCG 24-28 basedon genomic organization, order of domains and sequence homology. The phylogenetictree of the ABC transporters involved in cancer MDR is presented in Figure 1. A thick389