Development of multidrug resistance protein inhibitors
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abstract
Although a variety of combination regimens of chemotherapeutic agents are currently being used against neoplastic disorders, development of resistance to multiple anticancer drugs remains a major challenge for successful chemotherapy. Two protein pumps shown to cause this type of multidrug resistance in human tumor cells are the P-glycoprotein (PG-170) and the multidrug resistance peptide (MRP-190). Both proteins belong to the ABC superfamily of transport proteins which are structurally quite distinct in cell types and resistant patterns. Moreover, there may be crosstalk at the cellular level between altered partition model and pump model of development of multidrug resistance. However, no specific agent effective in reversing this protein-mediated development of resistance is available, except the general chemosensitizers such as verapamil, quinidine and ciclosporin which exhibited a low success rate. Various strategies are being used to discover multidrug resistance protein inhibitors such as competitive binding agents, protein antagonists, antisense oligonucleotides, leukotriene-D4 antagonists, chemosensitizers and selective inhibitors of protein function. Hopefully, future investigators will lead to successful selective inhibitors of multidrug resistance protein function and thus combat the development of resistance when given concurrently with chemotherapeutic agents.
