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Drug resistance in multiple myeloma
1Department of Hematology, University Hospital Rotterdam Dijkzigt, The Netherlands.
Abstract:
Multidrug resistance (MDR) is a pleiotropic resistance against several unrelated drugs. It may be induced by prolonged exposure of cells to drugs such as doxorubicin, etoposide and vinca alkaloids. Once MDR develops in clinical tumors, it is a major obstacle for the improvement of treatment of multiple myeloma (MM). Several specific mechanisms have been identified in clinical refractory MM patients including typical MDR, which is associated with P-glycoprotein (Pgp) and Lung Resistance Protein (LRP). The expression of the proteins associated with these genes seems to depend on exposure to chemotherapeutic agents. Recently, reversal of MDR by non-cytotoxic agents such as verapamil, cyclosporin A and PSC 833 (Valdospar) was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR is possible and that it may lead to alterations of the plasma pharmacokinetics of the cytostatic agents, in addition to P-glycoprotein inhibition in tumor cells. The potential implications of P-glycoprotein reversal are discussed.
Insights
Multidrug resistance (MDR) in multiple myeloma (MM) hinders treatment. Non-cytotoxic agents show potential for reversing MDR by inhibiting P-glycoprotein, improving chemotherapy effectiveness.
Area of Science:
- Oncology
- Pharmacology
Background:
- Multidrug resistance (MDR) presents a significant challenge in treating multiple myeloma (MM).
- MDR involves resistance to various chemotherapy drugs, often mediated by proteins like P-glycoprotein (Pgp) and Lung Resistance Protein (LRP).
Purpose of the Study:
- To explore the potential of non-cytotoxic agents in reversing MDR in multiple myeloma.
- To investigate the impact of MDR reversal on the pharmacokinetics of chemotherapeutic agents.
Main Methods:
- Review of recent clinical phase I/II trials investigating MDR reversal agents.
- Analysis of P-glycoprotein inhibition and its effects on tumor cells and drug pharmacokinetics.
Main Results:
- Preliminary results indicate that MDR reversal is achievable using agents like verapamil, cyclosporin A, and PSC 833 (Valdospar).
- MDR reversal may alter the plasma pharmacokinetics of cytostatic agents.
Conclusions:
- Reversal of MDR through P-glycoprotein inhibition offers a promising strategy to overcome treatment resistance in multiple myeloma.
- Further investigation into P-glycoprotein reversal has significant implications for enhancing MM therapy.