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.
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. 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.
