Related Experiment Videos
Keynote address: multidrug resistance: a pleiotropic response to cytotoxic drugs
1Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892.
Abstract:
Tumor cells exposed in tissue culture to one of several different classes of antineoplastic agents, including anthracyclines, vinca alkaloids, epipodophyllotoxins, and certain antitumor antibiotics, can develop resistance to the selecting agent and cross resistance to the other classes of agents. This phenomena of multidrug resistance is generally associated with decreased drug accumulation and overexpression of a membrane glycoprotein. This membrane protein, referred to as P-glycoprotein, apparently acts as an energy-dependent drug efflux pump. Multidrug resistance in human MCF-7 breast cancer cells selected for resistance to adriamycin (AdrR MCF-7) is associated with amplification and overexpression of the mdr1 gene which encodes P-glycoprotein. A number of other changes are also seen in this resistant cell line including alterations in Phase I and Phase II drug metabolizing enzymes. Similar biochemical changes occur in a rat model for hepatocellular carcinogenesis and are associated in that system with broad spectrum resistance to hepatotoxins. The similar changes in these two models of resistance suggests that these changes might be part of a battery of genes whose expression can be altered in response to cytotoxic stress, thus rendering the cell resistant to a wide variety of cytotoxic agents.
Insights
Cancer cells can develop multidrug resistance (MDR) to various chemotherapy drugs. This resistance is linked to P-glycoprotein, an efflux pump, and altered drug metabolism, suggesting a general stress response in cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Tumor cells can acquire resistance to multiple classes of antineoplastic agents, a phenomenon known as multidrug resistance (MDR).
- MDR is often associated with decreased drug accumulation and the overexpression of P-glycoprotein, a membrane protein acting as an energy-dependent drug efflux pump.
- In human MCF-7 breast cancer cells resistant to adriamycin (AdrR MCF-7), MDR is linked to mdr1 gene amplification and overexpression.
Purpose of the Study:
- To investigate the biochemical changes associated with multidrug resistance in cancer cells.
- To explore the role of P-glycoprotein and drug metabolizing enzymes in conferring cross-resistance to various cytotoxic agents.
- To compare resistance mechanisms in a human cancer cell line and a rat model of chemical carcinogenesis.
Main Methods:
- Exposure of tumor cells in tissue culture to different classes of antineoplastic agents.
- Analysis of drug accumulation and P-glycoprotein expression in resistant cell lines.
- Investigation of alterations in Phase I and Phase II drug metabolizing enzymes.
- Comparison of biochemical changes in resistant MCF-7 cells and a rat hepatocellular carcinogenesis model.
Main Results:
- Acquired resistance to one antineoplastic agent conferred cross-resistance to other drug classes.
- Multidrug resistance was associated with decreased intracellular drug levels and P-glycoprotein overexpression.
- The mdr1 gene, encoding P-glycoprotein, was amplified and overexpressed in adriamycin-resistant MCF-7 cells.
- Resistant cells also exhibited alterations in drug metabolizing enzymes, similar to changes observed in a rat hepatotoxin resistance model.
Conclusions:
- Multidrug resistance involves P-glycoprotein acting as a drug efflux pump, reducing intracellular drug concentrations.
- Alterations in drug metabolizing enzymes accompany P-glycoprotein-mediated resistance.
- The observed similarities in resistance mechanisms between human cancer cells and a rat carcinogenesis model suggest a conserved cellular response to cytotoxic stress.
- These findings indicate that cells may possess a coordinated battery of genes that can be activated to confer resistance against a broad spectrum of toxic agents.