Clinical reversal of multidrug resistance

Reversal of drug resistance offers the hope of increasing the efficacy of conventional chemotherapy, We tested dexverapamil as a P-glgcoprotein 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 11 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 1.65 mu mol/l and 1.58 mu mol/l, respectively, Since both are comparable antagonists, a median peak total reversing concentration of 3.24 mu mol/l was achieved, Pharmacokinetic analysis of doxorubicin and etoposide levels confirmed a delay in the clearance of doxoruhicin 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.