Reversing agents for ATP-binding cassette drug transporters.

Abstract

The multidrug resistance (MDR) phenotype exhibited by cancer cells is believed to be the major barriers to successful chemotherapy in cancer patients. The major form of MDR phenotype is contributed by a group of ATP-binding cassette (ABC) drug transporters which include P-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein. There has been intense search for compounds which can act to reverse MDR phenotype in cultured cells, in animal models, and ultimately in patients. The ongoing search for MDR modulators, compounds that act directly on the ABC transporter proteins to block their activity, has led to three generations of drugs. Some of the third-generation MDR modulators have demonstrated encouraging results compared to earlier generation MDR modulators in clinical trials. These modulators are less toxic and they do not affect the pharmacokinetics of anti-cancer drugs. Significant numbers of natural products have also been identified for their effectiveness in reversing MDR in a manner similar to the MDR modulators. Other MDR reversing strategies that have been studied quite extensively are also reviewed and discussed in this chapter. These include strategies aimed at destroying mRNAs for ABC drug transporters, approaches in inhibiting transcription of ABC transporter genes, and blocking of ABC transporter activity using antibodies. This review summarizes the development of reversing agents for ABC drug transporters up to the end of 2008, and provides an optimistic view of what we have achieved and where we could go from here.