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Clinical Reversal of Multidrug Resistance

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

Correspondence: Susan E. Bates, M.D., Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Building 10, Room 12N226, Bethesda, MD 20892, USA. Telephone: 301-496-4916; Fax: 301-402-0172.

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 fourfold 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.

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