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Anthracycline resistance.

E Friche1, T Skovsgaard, N I Nissen

  • 1Department of Internal Medicine, Finsen Institute, Copenhagen, Denmark.

Acta Oncologica (Stockholm, Sweden)
|January 1, 1989
PubMed
Summary
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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.

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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.