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Amplification and expression of genes associated with multidrug resistance in mammalian cells
Abstract:
In multidrug resistance, which is observed clinically and in tissue culture, cells that are challenged with certain cytotoxic drugs develop resistance not only to the selective agent but also to other, seemingly unrelated, agents. The multidrug-resistant phenotype is associated with DNA sequence amplification and with the overproduction of a number of cytosolic and membrane glycoproteins. The differential amplification and altered expression of at least two related genes, termed multidrug-resistant associated genes has been shown in multidrug-resistant Chinese hamster cells. In multidrug-resistant mouse and human cells, genes homologous to those in Chinese hamster cells are also amplified. The level of expression of these genes varied and did not correlate with their copy number. Furthermore, in Chinese hamster cells, the development of resistance to a single drug and multidrug resistance were closely related, but uncoupled, events. The overexpression of the multidrug-resistant genes was better correlated with the degree of resistance to the selective agent than it was with the extent of multidrug resistance.
Insights
Cells can develop multidrug resistance (MDR) by overexpressing specific genes, leading to cross-resistance against various drugs. Gene amplification and altered expression are key factors in this complex cellular defense mechanism.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Multidrug resistance (MDR) is a clinical challenge where cells become resistant to multiple drugs.
- This phenomenon is linked to DNA sequence amplification and overexpression of specific genes.
Purpose of the Study:
- To investigate the role of multidrug-resistant associated genes in MDR.
- To understand the relationship between gene amplification, expression, and drug resistance levels.
Main Methods:
- Analysis of gene amplification and expression in multidrug-resistant Chinese hamster, mouse, and human cells.
- Correlation studies between gene copy number, gene expression, and drug resistance phenotypes.
Main Results:
- Differential amplification and altered expression of multidrug-resistant associated genes were observed.
- Homologous genes were amplified in mouse and human MDR cells.
- Gene expression levels did not consistently correlate with copy number.
- Overexpression of MDR genes correlated better with resistance to the selective agent than with broad MDR.
Conclusions:
- Multidrug resistance involves complex genetic alterations and gene expression changes.
- The development of single-drug resistance and MDR are related but distinct processes.
- MDR gene overexpression is a significant factor in acquired drug resistance.