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-glgcoprot ein antagonist in combination with EPOCH chemotherapy in refractory no n-Hodgkin's lymphoma, In a cross-over design, dexverapamil was added t o 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-o ver to dexverapamil, Levels of mdr-1 were low before EPOCH, but increa sed four-fold or more in 42% of patients in whom serial samples were o btained, 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 antagonist s, a median peak total reversing concentration of 3.24 mu mol/l was ac hieved, Pharmacokinetic analysis of doxorubicin and etoposide levels c onfirmed a delay in the clearance of doxoruhicin ranging from 5% to 24 %; no change in the pharmacokinetics of etoposide was observed, This s tudy provides sufficient rationale for testing dexverapamil in a rando mized clinical trial.