Methotrexate inhbits dihydrofolate reductase, an enzyme important in DNA precursor synthesis. Cells grown in the presence of gradually increasing concentrations of methotrexate can adapt. 3000 X those that kill normal cells. Instability is correlated with the presence of very small chromosomes, double-minute chromosomes . Some organisms have evolved mechanisms of gene amplification to provide gene products needed in large quantities.
Amplification can be developmentally, temporally, or environmentally regulated.
Some gene amplifications, such as the MDM2 amplification, are associated with cancer.