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Multidrug resistance in lymphomas
Purpose:
To discuss the significance of multidrug resistance (MDR) in human lymphomas and to review recent and ongoing clinical trials using MDR modulators.
Design:
A medical literature search was used to identify articles that reported results on the expression or modulation of MDR in human lymphomas. This review summarizes the various methods for detecting expression of the mdr1 gene in tumor specimens, the patterns of expression in lymphomas, and recent and upcoming clinical trials using modulating agents to reverse MDR.
Results:
There is considerable variation in the assays used to evaluate the expression of mdr1 in lymphomas. Current methodology includes reverse transcriptase polymerase chain reaction (rt-PCR) for assay of mdr1 mRNA, and immunohistochemistry or flow cytometry for detection of the multidrug transporter, P-glycoprotein (P-gp). The preponderance of evidence suggests that mdr1 expression is relatively low in untreated patients (10% to 20% of lymphomas positive), but increases in patients with recurrent disease (50% to 70% positive). Some evidence suggests that mdr1 expression is a prognostic factor for response to chemotherapy, as well as for subsequent survival. Verapamil and cyclosporine (CsA) have been used as competitive inhibitors of the multidrug transporter P-gp in early clinical trials. Although these studies show some activity in modulating clinical MDR, both verapamil and CsA manifest considerable toxicities at doses below those required for complete inhibition of P-gp function.
Conclusion:
MDR due to the expression of the mdr1 gene is an important factor in the course of patients with lymphomas. Continued clinical trials with more potent and less toxic modulators are needed to define the ultimate benefit of modulating MDR in lymphomas.
Insights
Multidrug resistance (MDR) significantly impacts lymphoma treatment outcomes. Clinical trials exploring MDR modulators show promise but require more effective and safer agents for improved patient survival.
Area of Science:
- Oncology
- Pharmacology
Background:
- Multidrug resistance (MDR) poses a significant challenge in treating human lymphomas.
- The mdr1 gene and its product, P-glycoprotein (P-gp), are key mediators of MDR.
Purpose of the Study:
- To examine the role of MDR in human lymphomas.
- To review current clinical trials investigating MDR modulators.
Main Methods:
- Literature search for studies on MDR expression and modulation in lymphomas.
- Summary of detection methods for mdr1 gene expression (rt-PCR) and P-gp (immunohistochemistry, flow cytometry).
- Review of clinical trials using MDR modulators like verapamil and cyclosporine.
Main Results:
- MDR expression is low in untreated lymphomas (10-20%) but increases significantly in recurrent disease (50-70%).
- MDR expression may be a prognostic indicator for chemotherapy response and survival.
- Early trials with verapamil and cyclosporine showed some MDR modulation but were limited by toxicity.
Conclusions:
- MDR is a critical factor in lymphoma progression.
- Further research and development of potent, less toxic MDR modulators are essential for improving lymphoma treatment efficacy.