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The role of MDR-1 in refractory lymphoma
1National Institutes of Health, National Cancer Institute, Bethesda, MD 20892, USA.
Abstract:
Although lymphoma is one of the few solid tumours for which chemotherapy can be curative, the treatment of refractory lymphoma remains a major clinical problem. P-glycoprotein (Pgp), the drug efflux pump encoded by the MDR-1 gene is associated with multidrug resistance in several laboratory models of drug resistance, and a number of investigators have attempted to establish a role for Pgp in refractory lymphoma. Despite a considerable variability in the results of these studies investigating Pgp expression in lymphoma, the preponderance of the data suggests that Pgp may at least in part account for drug resistance in this disease. Several clinical trials using Pgp modulating compounds have attempted to reverse the drug resistant phenotype of refractory lymphoma. These studies, although difficult to interpret because of the effect of Pgp modulators on chemotherapeutic drug pharmacokinetics, also suggest a role for Pgp in mediating drug resistance in a subset of patients with refractory lymphoma. Studies with newer Pgp modulating agents with phase III designs will be needed before Pgp modulation can be considered for incorporation into routine oncologic practice.
Insights
P-glycoprotein (Pgp) may contribute to drug resistance in refractory lymphoma. Clinical trials suggest Pgp modulation may help treat some patients, but more research is needed for routine use.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Refractory lymphoma presents a significant clinical challenge, as chemotherapy can be curative for some lymphomas.
- P-glycoprotein (Pgp), encoded by the MDR-1 gene, is an efflux pump implicated in multidrug resistance.
- The role of Pgp in refractory lymphoma has been investigated, with variable but suggestive findings.
Purpose of the Study:
- To evaluate the role of P-glycoprotein (Pgp) in mediating drug resistance in refractory lymphoma.
- To assess the potential of Pgp modulating compounds in reversing the drug-resistant phenotype in lymphoma patients.
Main Methods:
- Review of existing studies investigating Pgp expression in lymphoma.
- Analysis of clinical trials evaluating Pgp modulating agents in refractory lymphoma.
- Consideration of pharmacokinetic effects of Pgp modulators on chemotherapy.
Main Results:
- Preponderance of data suggests Pgp contributes to drug resistance in lymphoma.
- Clinical trials indicate Pgp modulation may benefit a subset of refractory lymphoma patients.
- Interpreting trial results is complicated by Pgp modulators' pharmacokinetic effects.
Conclusions:
- P-glycoprotein likely plays a role in drug resistance in refractory lymphoma.
- Pgp modulation shows promise for a subset of patients, but requires further investigation.
- Phase III trials with novel Pgp modulators are necessary before clinical adoption.
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