P-gp-mediated drug resistance

There has been considerable interest in the potential use of P-gp inhibition to optimize pharmacotherapy of anticancer and antiretroviral agents. Significant efforts have been made to exploit P-gp blockade in an effort to enhance chemotherapy uptake in tumors expressing P-gp-mediated drug resistance, to improve chemotherapy bioavailability, and to increase exposure to tumors protected by the blood-brain barrier. Research is also being directed at using P-gp inhibitors in HIV patients to improve protease inhibitor uptake into T-lymphocytes and virologic sanctuaries such as the brain and testes. 

CYP3A substrate CYP oxidation to alkylating dehydromonocrotaline Metabohzation by CYP2A6 inhibition of CYP2E1 CYPlAl inducer Reversal of P-gp mediated drug resistance in KB-Vl cells and in NCr n/ nu mice... 

A specific inhibitor of BCRP is the tremorgenic mycotoxin fumitremorgin C (FTC). FTC blocked mitoxantrone transport by BCRP without affecting P-gp or MRPl-mediated drug resistance (Rabindran et al., 2000). However, due to neurotoxic effects in vivo apvplication is still not possible. 

Apoptotic intercalator reversal of P-gp (245,334) mediated drug resistance Inhibition of CYPlAl, detoxification by (326)... 

Multidrug resistance (MDR) is the name ascribed to the phenomenon whereby cancer cells and tumors develop resistance to chemotherapeutic agents. Conceptually, this can be viewed as a survival response whereby cancer cells endeavor to ward off cytotoxic compounds. Mechanistically, MDR is typically mediated by overexpression of P-glycoprotein (P-gp aka ABCB1) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. 

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