Multidrug resistance: a transport system of antitumor agents and xenobiotics

Abstract

Resistance of tumors to a variety of chemotherapeutic agents presents a major problem in cancer treatment. Resistance to such agents as doxorubicin, Vinca alkaloids, and actinomycin D can be acquired by tumor cells after treatment with a single drug. The gene responsible for multidrug resistance, termed mdr1, encodes a membrane glycoprotein (P-glycoprotein) that acts as a pump to transport various cytotoxic agents including various xenobiotics out of the cell. The amount of P-glycoprotein expression has been measured in tumor samples and was found to be elevated in intrinsically drug-resistant cancers of the colon, kidney, and adrenal as well as in some tumors that acquired drug resistance after chemotherapy. The protein was also found to be elevated in cells treated with xenobiotics. P-glycoprotein has been shown to bind anticancer drugs and several resistance-reversing agents including calcium channel blockers, and to be an ATPase. We recently reconstituted the purified P-glycoprotein into artificial liposomes. Reconstituted P-glycoprotein showed ATPase activity, ATP-dependent drug-transport activity, and calcium channel blocker-binding activity. This model provides many advantages for studies of the biochemical functions of P-glycoprotein. In addition to these basic interests, the protein is of considerable interest as a target for cancer chemotherapy because it appears to be involved in both acquired multidrug resistance and intrinsic drug resistance in human cancer. The selective killing of tumor cells expressing P-glycoprotein could be very important in future cancer therapy.