Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, and is a crucial enzyme for the synthesis of purines, pyrimidines and some amino acids. Inhibition of the activity of this enzyme leads to arrest of DNA synthesis and cell death. Gene expression of methotrexate (MTX)-resistant variants of DHFR in normal hematopoietic cells is a potential strategy to permit administration of larger doses of MTX by alleviating drug toxicity in normal cells and tissues that are drug sensitive.