Unstable Methotrexate Resistance in Human Small-Cell Carcinoma Associated with Double Minute Chromosomes

Resistance to antineoplastic drugs may develop through a variety of mechanisms, including deletion of membrane-transport mechanisms, an increase in target-enzyme concentration, or a deletion of an essential drug-activating enzyme. One unique mechanism for mutation to drug resistance is amplification of the gene coding for a target protein, leading to elevated levels of the protein. In studies of cultured experimental tumor-cell lines, resistance to a variety of toxic substances, including cadmium¹ and the antineoplastic drugs N-phosphonacetyl-L-aspartate² and methotrexate,³ has been ascribed to gene amplification. The process of gene amplification in methotrexate-resistant mammalian cells may occur within a single chromosome, producing an.