Fifth Gordon Hamilton-Fairley memorial lecture. Methotrexate resistance and gene amplification: an experimental model for the generation of cellular heterogeneity.

Gene amplification is a mechanism whereby cultured animal cells and human tumours become resistant to cancer chemotherapeutic agents. This review of studies from the authors' laboratory describes properties of the acquisition of resistance to methotrexate in cultured mammalian cells by virtue of amplification of the dihydrofolate reductase gene. These properties result in a heterogeneous cell population with respect to many cell properties, including the number and stability of the amplified genes. Gene amplification results from overreplication of DNA in a single cell cycle as a result of inhibition of DNA synthesis. The cells surviving such overreplication constitute a heterogeneous population with multiple chromosomal changes, including partial or complete endoreduplication of chromosomes, as well as a variety of chromosomal rearrangements. A similar phenomenon may underlie the generation of aneuploidy in tumours, their malignant progression, and the generation of heterogeneity in the tumour cell population.