Gene amplification and altered enzymes as mechanisms for the development of drug resistance

Two known mechanisms by which neoplastic cells may become resistant to chemotherapeutic agents are reviewed, using methotrexate (MTX) resistance as a model. These mechanisms are an increased level of target enzyme, found in several instances to be a consequence of gene amplification, or an altered target enzyme or receptor, less capable of binding the drug. An example of MTX resistance due to low-level gene amplification in leukemia cells from an MTX-resistant patient is described. Strategies for selectively eradicating these resistant cell populations may be formulated based on the mechanism by which these cells became drug-resistant.