A Closer Look at Drug Resistance: Methotrexate
Understanding the functions of methotrexate has led to a better understanding of the development of drug resistance. There are three known ways in which a cell may acquire immunity to the effects of this folate antagonist.
Decreased concentration of the drug in the cell: The concentration of methotrexate in the cell can be diminished by a change in the transport system that moves the drug into the cell. If there is reduction in the number of channels through which methotrexate can move, less will be found within the cell. Also, the concentration of the drug in the cell can be regulated by the altered rates of metabolism. When the drug is metabolized it is more easily removed from the cell, decreasing its concentration and activity within the cell.(1)
Increased concentration of DHFR in the cell: Amplification of the DHFR gene causes an increase in the amount of DHFR present and has been shown to correlate with reduced response to methotrexate treatment.(1)
Mutations in DHFR that reduce DHFR:methotrexate binding: methotrexate must bind to DHFR to prevent its activity. If a genetic change alters the binding region of DHFR in a way that reduces methotrexate binding, DHFR will continue to activate folates and the effectiveness of the treatment will decrease.(1)
All of these outcomes have been implicated in the increased resistance to methotrexate. Acquired resistance to methotrexate is one of the primary complications of treatment with the drug.(2)
Resistance to chemotherapy drugs is a key factor in the failure of many treatments.