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Multidrug resistance
1Finnish Red Cross, Blood Transfusion Service, Helsinki.
Abstract:
Resistance of malignant cells to cytotoxic agents is often a limiting factor to successful chemotherapy. The classical multidrug resistance is characterised by overexpression of a membrane protein, P-glycoprotein, which acts like a drug extruding pump reducing accumulation of cytotoxic agents inside malignant cells, thereby preventing their function. Resistance is expressed simultaneously towards several structurally unrelated drugs. P-glycoprotein is also expressed in many normal human tissues, e.g., in the gastrointestinal tract, and this may be the reason for intrinsic resistance observed clinically in cancers derived from certain tissues. More often multidrug resistance is acquired during chemotherapy. The physiological function of P-glycoprotein is still unknown but it may have a role in cellular detoxification and secreting mechanisms. Interest in the phenomenon of multidrug resistance centres on the correlation of P-glycoprotein expression to clinical drug resistance. Another goal is to find mechanisms by which the function of P-glycoprotein as a multidrug transporter is prevented and drug resistance reversed.
Insights
Malignant cells develop multidrug resistance (MDR) via P-glycoprotein, a pump that reduces drug accumulation. Understanding and reversing this P-glycoprotein function is key to improving chemotherapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant cell resistance to chemotherapy limits treatment success.
- Multidrug resistance (MDR) is often mediated by P-glycoprotein (P-gp) overexpression.
- P-gp acts as an efflux pump, reducing intracellular cytotoxic drug concentrations.
Purpose of the Study:
- To explore the role of P-glycoprotein in multidrug resistance.
- To investigate the correlation between P-glycoprotein expression and clinical drug resistance.
- To identify strategies for preventing P-gp function and reversing drug resistance.
Main Methods:
- Analysis of P-glycoprotein expression in malignant cells.
- Correlation studies between P-gp levels and patient response to chemotherapy.
- Investigation of potential mechanisms to inhibit P-gp activity.
Main Results:
- P-glycoprotein overexpression is linked to simultaneous resistance to multiple unrelated drugs.
- P-gp is present in normal tissues, potentially contributing to intrinsic resistance.
- Acquired multidrug resistance during chemotherapy is frequently associated with P-gp.
Conclusions:
- P-glycoprotein is a significant factor in both intrinsic and acquired multidrug resistance.
- Targeting P-glycoprotein offers a potential strategy to overcome chemotherapy resistance.
- Further research is needed to elucidate P-gp's physiological role and therapeutic inhibition.