DHFR and cancer: The same principle has been observed to be responsible for the development of drug-resistant cancer cells; in some cases, drug resistance appears to result from the selection of tumor phenotypes produced by genetic mutations (generally gene amplifications) that confer resistance to the cell killing effects of specific types anti-cancer drugs, such as the amplification of the mdr-1 gene, associated with a multi-drug-resistant phenotype and the dihydrofolate reductase (DHFR) gene, which specifically confers resistance to the folate antagonists (e.g., methotrexate; Schimke, 1988).