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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Clinical Reversal of Multidrug Resistance
1Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, 20892, USA.
Dexverapamil, a P-glycoprotein antagonist, showed objective responses when combined with EPOCH chemotherapy in refractory non-Hodgkin's lymphoma. This combination therapy warrants further investigation in randomized clinical trials for drug-resistant cancers.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Drug resistance limits conventional chemotherapy efficacy.
- P-glycoprotein (P-gp) is a key mediator of multidrug resistance.
- Refractory non-Hodgkin's lymphoma (NHL) presents a significant clinical challenge.
Purpose of the Study:
- To evaluate dexverapamil as a P-gp antagonist in combination with EPOCH chemotherapy.
- To assess the efficacy and safety of this combination in patients with refractory NHL.
- To investigate the impact of dexverapamil on P-gp expression and drug pharmacokinetics.
Main Methods:
- A cross-over design study combining dexverapamil with EPOCH chemotherapy.
- Monitoring objective responses in assessable patients.
- Analyzing mdr-1 gene expression via biopsies.
- Conducting pharmacokinetic analyses of dexverapamil, nor-dexverapamil, doxorubicin, and etoposide.
Main Results:
- Objective responses were observed in 10 of 41 assessable patients.
- Mdr-1 levels increased significantly (fourfold or more) in 42% of patients after EPOCH treatment.
- Dexverapamil achieved a median peak total reversing concentration of 3.24 µmol/l.
- A delay in doxorubicin clearance (5-24%) was noted, with no change in etoposide pharmacokinetics.
Conclusions:
- Dexverapamil shows potential as a P-gp antagonist to overcome chemotherapy resistance in refractory NHL.
- The observed drug interactions and mdr-1 modulation support further clinical evaluation.
- This study provides a rationale for randomized clinical trials of dexverapamil combined with EPOCH chemotherapy.
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