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Published on: September 10, 2018
Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies
Abstract:
One reason for the failure of chemotherapy in the treatment of advanced cancers may be the outgrowth of multidrug-resistant tumour cells. Multidrug resistance has been modelled in numerous mammalian cell lines in which the phenotype is characterized by a pleiotropic cross-resistance to unrelated drugs. In the study reported here, we have produced monoclonal antibodies whose binding to plasma membranes of different multidrug-resistant mammalian cells correlates with the degree of drug resistance. All these antibodies are specific for P-glycoprotein, a cell surface component of relative molecular mass (Mr) 170,000 (170K) that has been described previously, and are directed against three spatially distinct epitopes which define a conserved cytoplasmic domain in the C-terminal region of the P-glycoprotein polypeptide. The conserved nature of P-glycoprotein and its low-level expression is drug-sensitive cells suggest that it has an important function at the cell surface. The monoclonal antibodies against P-glycoprotein described here might serve as diagnostic reagents for clinically unresponsive tumours.
Insights
Multidrug resistance in cancer may stem from P-glycoprotein. New monoclonal antibodies targeting this protein show promise as diagnostic tools for identifying drug-resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Chemotherapy failure in advanced cancers is often linked to multidrug-resistant (MDR) tumor cells.
- MDR is characterized by cross-resistance to various unrelated drugs in mammalian cell lines.
- P-glycoprotein (P-gp) is a known cell surface component associated with MDR.
Purpose of the Study:
- To develop and characterize monoclonal antibodies (mAbs) that bind to plasma membranes of MDR cells.
- To investigate the correlation between mAb binding and the degree of drug resistance.
- To explore the diagnostic potential of these mAbs for MDR tumors.
Main Methods:
- Production of monoclonal antibodies against plasma membranes of multidrug-resistant mammalian cells.
- Characterization of antibody specificity for P-glycoprotein (170K).
- Mapping of antibody binding sites to distinct epitopes on P-glycoprotein.
Main Results:
- Monoclonal antibodies were generated that bind to plasma membranes of MDR cells.
- Antibody binding intensity correlated with the level of drug resistance.
- All antibodies were specific for P-glycoprotein, targeting conserved cytoplasmic epitopes.
- P-glycoprotein's conserved nature and low expression in drug-sensitive cells suggest a crucial cell surface function.
Conclusions:
- Monoclonal antibodies against P-glycoprotein can be produced.
- These antibodies correlate with drug resistance levels in cancer cells.
- The generated monoclonal antibodies show potential as diagnostic reagents for identifying clinically unresponsive (MDR) tumors.
