title: Clinical Reversal of Multidrug Resistance.
abstract: 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.
authors.affiliation: Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.initials: SE
authors.lastname: Bates
authors.initials: WH
authors.lastname: Wilson
authors.initials: AT
authors.lastname: Fojo
authors.initials: M
authors.lastname: Alvarez
authors.initials: Z
authors.lastname: Zhan
authors.initials: J
authors.lastname: Regis
authors.initials: R
authors.lastname: Robey
authors.initials: C
authors.lastname: Hose
authors.initials: A
authors.lastname: Monks
authors.initials: YK
authors.lastname: Kang
authors.initials: B
authors.lastname: Chabner