Cancer Drug Resistance: Multiple Drug Resistance (MDR)
Failure of the drugs to enter the target cell and/or drug ejection: There are several reasons why drugs may not reach therapeutic levels within cancer cells. One of the most frequent problems is the amplification of a gene commonly known as MDR1 for multiple drug resistance. Another common name for this same protein is the P-glycoprotein. This gene encodes a large transmembrane protein that has the ability to a) stop certain drugs from entering a cell and b) eject drugs from the cell once they have entered. This combination of capabilities makes the MDR protein very effective at reducing intracellular concentrations of a variety of chemotherapy agents. While the normal function of this protein has nothing to do with chemotherapy drugs, it is quite often the reason for chemotherapy drug failure. The prevention of drug entry and drug ejection are depicted in the animation below.(1)
The importance of MDR mediated drug resistance is underscored by the fact that several drugs designed to inhibit the activity of this protein are currently under investigation.(2) In addition, MDR is being examined as a gene therapy treatment that could be used to increase drug tolerance in individuals undergoing chemotherapy. The MDR gene is being inserted into bone marrow stem cells which are then placed back into the patient. The increased expression of MDR in the bone marrow cells renders them less susceptible to the harmful effects of the drugs and allows the patient to tolerate higher doses of the chemotherapy drugs. It is hoped that the increased levels of the drugs will more effectively eliminate the cancer.(3)
Carpinteiro A, Peinert S, Ostertag W, Zander AR, Hossfeld DK, Kuhlcke K, Eckert HG, Baum C, Hegewisch-Becker S. "Genetic protection of repopulating hematopoietic cells with an improved MDR1-retrovirus allows administration of intensified chemotherapy following stem cell transplantation in mice."
Int J Cancer (Apr 10 2002). 98(5):785-92. [PUBMED]
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