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Detection of multidrug resistance gene expression in multiple myeloma
1Moffitt Cancer Center, University of South Florida, Tampa 33612-9497, USA.
Abstract:
Multiple myeloma is a disease which is generally considered responsive to chemotherapy; however, essentially all patients who respond to drug treatment will relapse and die of drug-resistant disease. This disease is therefore considered a paradigm for studying the development of acquired drug resistance in the clinic. Natural product agents are frequently used in the treatment of myeloma, especially vincristine and doxorubicin. Studies using human myeloma cell lines have shown that the MDR1 gene product, P-glycoprotein (Pgp), is responsible for conferring drug resistance to natural products and glucocorticoids. We have developed assays to measure the expression of MDR1/Pgp in human myeloma specimens. These assays include immunocytochemistry, flow cytometry, and RT/PCR. Human myeloma cell lines, 8226/Dox, that are resistant to natural product agents and overexpress MDR1/Pgp are important for standardizing results and offer a means of comparing inter- and intra-patient results. Assays which measure both the presence and function of Pgp are necessary to determine the role of Pgp in clinical drug resistance in patients with myeloma.
Insights
Drug resistance in multiple myeloma is a major challenge. Measuring P-glycoprotein (Pgp) expression using new assays is crucial for understanding and overcoming treatment resistance in patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multiple myeloma is typically responsive to chemotherapy, but acquired drug resistance leads to relapse and mortality.
- Natural product agents like vincristine and doxorubicin are common in myeloma treatment.
- The MDR1 gene product, P-glycoprotein (Pgp), is implicated in resistance to these agents.
Purpose of the Study:
- To develop and validate assays for measuring MDR1/Pgp expression in human myeloma specimens.
- To establish standardized methods for assessing Pgp in clinical drug resistance.
- To compare inter- and intra-patient results using validated assays.
Main Methods:
- Development of assays including immunocytochemistry, flow cytometry, and RT/PCR.
- Utilization of human myeloma cell lines (8226/Dox) overexpressing MDR1/Pgp for standardization.
- Measurement of both the presence and function of Pgp.
Main Results:
- Established assays capable of measuring MDR1/Pgp expression in human myeloma.
- Validated the utility of drug-resistant cell lines for assay standardization.
- Demonstrated the necessity of assessing both Pgp presence and function.
Conclusions:
- Accurate measurement of MDR1/Pgp expression is essential for understanding clinical drug resistance in multiple myeloma.
- Validated assays provide a means to standardize and compare Pgp assessment across patients.
- Further investigation into the role of Pgp is critical for improving myeloma treatment outcomes.