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Abstract:
Multidrug resistance describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. This phenotype occurs frequently in mammalian cell lines and transplantable tumours selected for resistance to a single drug. Reduced cellular accumulation of the drugs involved appears to account for the resistance. This may be a consequence of reduced drug influx, increased drug efflux, or both. A wide variety of biochemical changes have been identified in multidrug resistant cell lines, the most consistent of which is the increased expression of P-glycoprotein, a conserved, high molecular weight, plasma membrane glycoprotein. The level of P-glycoprotein expression correlates with the degree of drug resistance in a variety of different cell types. In a number of multidrug resistant cell lines, overexpression of P-glycoprotein results from gene amplification. While the function of P-glycoprotein is unknown, independent lines of evidence support the notion that P-glycoprotein is the causative molecule mediating the multidrug resistance phenotype. Significant levels of P-glycoprotein expression have been detected in some biopsy specimens from patients with ovarian and sarcoma tumours. These findings suggest that multidrug resistant tumour cells can occur in human malignancies. The presence of such cells may affect the outcome of chemotherapy.
Insights
Multidrug resistance, characterized by resistance to multiple anticancer drugs, is often linked to reduced drug accumulation. P-glycoprotein, a plasma membrane protein, is consistently overexpressed in resistant cells and may drive this phenomenon.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) is a complex phenotype where cells resist diverse cytotoxic compounds, including anticancer agents.
- This resistance is frequently observed in cell lines and tumors selected for single-drug resistance.
- Reduced cellular drug accumulation, due to altered influx or efflux, underlies this resistance.
Purpose of the Study:
- To investigate the molecular mechanisms contributing to multidrug resistance.
- To identify key cellular changes associated with the multidrug resistance phenotype.
- To explore the role of P-glycoprotein in mediating drug resistance.
Main Methods:
- Selection of mammalian cell lines and transplantable tumors for drug resistance.
- Analysis of cellular drug accumulation and transport.
- Biochemical characterization of resistant cell lines, focusing on protein expression.
- Investigation of gene amplification in multidrug resistant cells.
Main Results:
- Reduced cellular accumulation of drugs is a primary feature of multidrug resistance.
- Increased expression of P-glycoprotein, a plasma membrane glycoprotein, is consistently observed in resistant cells.
- P-glycoprotein expression levels correlate with the degree of drug resistance.
- Gene amplification of P-glycoprotein observed in some resistant cell lines.
- P-glycoprotein detected in human ovarian and sarcoma tumors, suggesting its role in clinical malignancies.
Conclusions:
- P-glycoprotein is strongly implicated as the causative molecule mediating the multidrug resistance phenotype.
- The presence of multidrug resistant tumor cells expressing P-glycoprotein in human cancers may impact chemotherapy outcomes.
- Further research into P-glycoprotein function and its role in cancer is warranted.