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Search for specific inhibitors of multidrug resistance in cancer
1National Institute of Haematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences, Hungary.
Abstract:
This paper deals with the theoretical background, methods and clinical significance of the search for specific inhibitors of multidrug resistance (MDR) in cancer. After discussing the basic features of the drug pump membrane proteins (MDR1 and MRP) responsible for this phenomenon, the possible mechanism of action of MDR inhibitors is reviewed. Modulators of drug pump expression may include inhibitors of the transcription and translation, as well as the processing and post-translational modifications of MDR1 and MRP. The function of the drug pumps can be effectively inhibited by substrate analogs, inhibitors of ATP-binding and utilization, specific monoclonal antibodies, and by various agents with still non-specified mechanisms. Basic methods are presented for the in vitro screening of MDR inhibitors in whole cells and in pump protein preparations, as well as for the in vivo assessment of the efficiency and safety of such inhibitors. The review also discusses some current problems and perspectives of MDR modulation in clinical tumor therapy.
Insights
This study reviews methods for finding cancer multidrug resistance (MDR) inhibitors. It covers drug pump proteins, inhibitor mechanisms, screening techniques, and clinical applications for improved cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) in cancer arises from drug pump membrane proteins like MDR1 and MRP.
- Understanding these proteins is crucial for developing effective cancer treatments.
Purpose of the Study:
- To review the theoretical background, methods, and clinical significance of searching for MDR inhibitors.
- To explore mechanisms of action for MDR inhibitors and their role in cancer therapy.
Main Methods:
- Discusses modulators of drug pump expression (transcription, translation, post-translational modifications).
- Reviews various inhibition strategies: substrate analogs, ATP-binding inhibitors, monoclonal antibodies, and agents with unknown mechanisms.
- Presents in vitro screening methods using whole cells and protein preparations.
- Includes in vivo assessment of inhibitor efficiency and safety.
Main Results:
- Identifies key drug pump proteins (MDR1, MRP) responsible for MDR.
- Outlines diverse mechanisms by which MDR inhibitors can function.
- Details established and novel methods for screening and evaluating MDR inhibitors.
Conclusions:
- MDR modulation holds significant potential for clinical tumor therapy.
- Further research into current problems and future perspectives is essential for advancing MDR inhibitor development.