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Clinical Reversal of Multidrug Resistance

Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, USA

Key Words. Multidrug resistance • P-glycoprotein • Lymphoma • Chemotherapy • Antagonist • Verapamil

Dr. Susan E. Bates, Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bldg. 10, Rm. 12N226, Bethesda, MD 20892, USA.

Reversal of drug resistance offers the hope of increasing the efficacy of conventional chemotherapy. We tested dexverapamil as a P-glycoprotein antagonist in combination with EPOCH chemotherapy in refractory non-Hodgkin's lymphoma. In a cross-over design, dexverapamil was added to EPOCH after disease stabilization or progression occurred. Objective responses were observed in 10 of 41 assessable patients. Biopsies for mdr-1 were obtained before EPOCH treatment and at the time of cross-over to dexverapamil. Levels of mdr-1 were low before EPOCH, but increased four-fold or more in 42% of patients in whom serial samples were obtained. Pharmacokinetic analysis revealed median peak concentrations of dexverapamil and its metabolite, nor-dexverapamil, of 1.66 µmol/l and 1.58 µmol/l, respectively. Since both are comparable antagonists, a median peak total reversing concentration of 3.24 µmol/l was achieved. Pharmacokinetic analysis of doxorubicin and etoposide levels confirmed a delay in the clearance of doxorubicin ranging from 5% to 24%; no change in the pharmacokinetics of etoposide was observed. This study provides sufficient rationale for testing dexverapamil in a randomized clinical trial.

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