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Modulation of multidrug resistance (MDR) in hematological malignancies
1Novartis Pharma AG, Basel, Switzerland. alfredo.covelli@pharma.novartis.com
Summary
Multidrug resistance (MDR) in blood cancers involves P-glycoprotein (P-gp) overexpression. Third-generation modulators like valspodar show promise in reversing MDR safely, with ongoing trials defining clinical benefits.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a significant challenge in treating hematological malignancies, characterized by tumor cells becoming resistant to multiple chemotherapeutic agents.
- Overexpression of P-glycoprotein (P-gp), encoded by the human MDR1 gene, is a primary mechanism driving MDR in cancers like acute myelogenous leukemia (AML), multiple myeloma (MM), and non-Hodgkin's lymphoma (NHL).
- Previous attempts to reverse P-gp-mediated MDR using 'off-the-shelf' compounds were often limited by severe toxic effects and pharmacokinetic alterations.
Purpose of the Study:
- To evaluate the safety and efficacy of third-generation MDR modulators, specifically valspodar, in reversing P-gp-mediated multidrug resistance.
- To assess the potential of valspodar in combination chemotherapy regimens for hematological malignancies.
- To determine the clinical benefits and full extent of MDR modulation in patients with AML, MM, and NHL.
Main Methods:
- Phase I/IIa clinical trials were conducted to assess the safety of valspodar in combination with chemotherapy.
- Dose adjustments of P-gp substrate chemotherapy agents were implemented when used with valspodar.
- MDR reversal by valspodar was evaluated in patients diagnosed with AML, multiple myeloma, and non-Hodgkin's lymphoma.
Main Results:
- Third-generation MDR modulators, including valspodar, can be safely administered in combination with chemotherapy regimens after appropriate dose adjustments.
- Valspodar demonstrated MDR reversal in patients with AML, multiple myeloma, and non-Hodgkin's lymphoma.
- Ongoing randomized phase III trials are crucial for definitively establishing the clinical benefits of valspodar.
Conclusions:
- Valspodar represents a promising third-generation MDR modulator for hematological malignancies.
- Safe administration and MDR reversal have been observed, but definitive clinical benefits await further phase III trial results.
- Further research is needed to fully elucidate the role of MDR modulators in optimizing chemotherapy for blood cancers.