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[Multi-drug resistance and myelodysplastic syndromes: a possible role for remission inducing agents?]
1Service des Maladies du Sang, Hôpital Huriez, CHU Lille, France.
Abstract:
Expression of P-glycoprotein (PGP), the product of the multidrug resistance gene (mdr1), is common in myelodysplastic syndromes (MDSs) and explains in part the low rate of complete remissions (CRs) obtained after aggressive chemotherapy. Reversion of the mdr phenotype to restore chemosensitivity has been the focus of many studies over the last ten years. Two phase III studies evaluated quinine for obtaining reversion of mdr gene expression in MDSs treated by aggressive chemotherapy. Results suggested better response rates and longer survival times in quinine-treated MDR-positive patients. However, the toxicity of quinine warrants further work aimed at developing other mdr phenotype reversion-inducing agents. Some such agents have proved superior over quinine in in vitro studies. Reversion of other mechanisms underlying chemoresistance in MDSs is a promising avenue of research.
Insights
Multidrug resistance in myelodysplastic syndromes (MDSs) limits chemotherapy effectiveness. Quinine showed promise in reversing this resistance, improving outcomes for MDR-positive MDS patients, but safer alternatives are needed.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- P-glycoprotein (PGP) expression, encoded by the multidrug resistance (mdr1) gene, is prevalent in myelodysplastic syndromes (MDSs).
- This PGP expression contributes to chemoresistance and low complete remission (CR) rates in MDS patients undergoing aggressive chemotherapy.
- Restoring chemosensitivity by reversing the multidrug resistance (mdr) phenotype is a critical research area.
Purpose of the Study:
- To evaluate the efficacy of quinine in reverting mdr gene expression in MDS patients.
- To assess the impact of quinine treatment on response rates and survival in MDR-positive MDS patients.
Main Methods:
- Two Phase III clinical studies were conducted.
- Patients with MDS received aggressive chemotherapy, with some treated with quinine to induce reversion of mdr gene expression.
Main Results:
- Quinine treatment was associated with improved response rates and longer survival times in MDR-positive MDS patients.
- However, quinine's toxicity necessitates the development of alternative agents.
Conclusions:
- Reversion of the mdr phenotype is a viable strategy to enhance chemotherapy efficacy in MDS.
- While quinine showed benefits, its toxicity highlights the need for safer mdr phenotype reversion-inducing agents.
- Investigating other mechanisms of chemoresistance in MDS is a promising future research direction.