Clinical Reversal of Multidrug Resistance

• Published in: The oncologist (Dayton, Ohio) Ohio), 1996-08, Vol.1 (4), p.269-275
• Main Authors: Bates, Susan E., Wilson, Wyndham H., Fojo, Antonio T., Alvarez, Manuel, Zhan, Zhirong, Regis, Joanna, Robey, Rob, Hose, Curtis, Monks, Anne, Kang, Yoon Koo, Chabner, Bruce
• Format: Article
• Language: English
• Subjects: Antagonist; Chemotherapy; Lymphoma; Multidrug resistance; P‐glycoprotein; Verapamil
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.1-4-269

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.