Clinical reversal of multidrug resistance.

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Bates SE, Wilson WH, Fojo AT, Alvarez M, Zhan Z, Regis J, Robey R, Hose C, Monks A, Kang YK, Chabner B

Clinical reversal of multidrug resistance.

Stem Cells. 1996 Jan;14(1):56-63. doi: 10.1002/stem.140056.

PubMed ID

8820952 [ View in PubMed

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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 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 mumol/l and 1.58 mumol/l, respectively. Since both are comparable antagonists, a median peak total reversing concentration of 3.24 mumol/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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dexverapamil	P-glycoprotein 1	Protein	Humans	Yes	Inhibitor	Details