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Anthracycline resistance
E Friche1, T Skovsgaard, N I Nissen
1Department of Internal Medicine, Finsen Institute, Copenhagen, Denmark.
Abstract:
The major limitation of the usefulness of anthracyclines is the development of drug resistance. Most of the data related to anthracycline resistance has been obtained in experimental animal tumors or in cultured human cell lines. An important characteristic obtained in these models is the common finding of cross-resistance to a series of drugs structurally unrelated to the anthracyclines and with a mechanism of action which apparently differ from that of the anthracyclines. This phenomenon is defined as pleiotropic drug resistance or multidrug resistance (MDR). The cross-resistance demonstrated includes the vinca alkaloids, actinomycin D, colchicin and the epipodophyllotoxins. The best documented mechanism of resistance and mechanism of cross-resistance is decreased cellular drug accumulation. Several findings indicate that the underlying factor of the altered net uptake is an active drug extrusion in the resistant cells. Another important characteristic is the demonstration of a cell surface protein with a molecular weight of about 170,000 (GP 170). Genetic and biochemical evidence indicate that the MDR phenotype in both animal and human cells result from overexpression of the MDR-1 gene which encodes GP 170. Some findings suggest that GP 170 is a transport protein for cytotoxic hydrophobic drugs like the anthracyclines. Other findings suggest that this gene is also associated with intrinsic (natural) anthracycline resistance.
Insights
Drug resistance limits anthracycline effectiveness, often causing cross-resistance to unrelated drugs. This multidrug resistance (MDR) is linked to the MDR-1 gene and a cell surface protein (GP 170) that may actively pump drugs out of cells.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Anthracyclines are vital chemotherapy agents, but their clinical utility is significantly hampered by the development of drug resistance.
- Drug resistance in cancer cells often manifests as multidrug resistance (MDR), a phenomenon where cells become resistant to a wide range of structurally and mechanistically diverse drugs.
Purpose of the Study:
- To elucidate the mechanisms underlying anthracycline resistance and multidrug resistance (MDR).
- To investigate the role of specific cellular components and genetic factors in conferring MDR phenotype.
Main Methods:
- Studies utilized experimental animal tumors and cultured human cell lines to model anthracycline resistance.
- Analysis involved characterizing drug accumulation, drug extrusion mechanisms, and identifying key cellular proteins and genes associated with resistance.
Main Results:
- A common characteristic of resistant cells is cross-resistance to unrelated drugs, defining the MDR phenomenon.
- The primary mechanism identified is decreased cellular drug accumulation due to active drug extrusion.
- Overexpression of the MDR-1 gene, encoding a 170,000 molecular weight cell surface protein (GP 170), was strongly associated with the MDR phenotype.
Conclusions:
- The MDR phenotype, including resistance to anthracyclines, is largely attributed to the overexpression of the MDR-1 gene and its product, GP 170.
- GP 170 is proposed to function as a drug efflux pump, actively removing cytotoxic drugs from resistant cells.
- This research provides critical insights into the molecular basis of multidrug resistance, potentially informing strategies to overcome treatment failures in cancer therapy.