Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model

Manfred Lehnert, William S. Dalton, Denise Roe, Scott Emerson, Sydney E. Salmon

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Abstract

In an effort to develop a clinically useful approach to overcoming P-glycoprotein-mediated multidrug resistance (MDR1), we evaluated combined chemosensitization with verapamil and quinine in a multidrug-resistant (MDR) human myeloma cell line model. In clonogenic assay, verapamil was used at concentrations from 0.1 to 1.0 μg/mL, bracketing the plasma levels achieved by oral administration and high-dose intravenous (IV) infusion, respectively. The dose of quinine was held constant at 1.0 μg/mL, a plasma concentration readily achieved by oral administration. At each dose level of verapamil tested, the combination with quinine proved more effective than either drug individually in reversing resistance to doxorubicin and vinblastine and synergistic chemosensitizing interaction was observed. Verapamil at 0.1 μg/mL combined with quinine was capable of restoring sensitivity to doxorubicin fully and reduced resistance to vinblastine as effectively as verapamil alone at 1.0 μg/mL. Furthermore, the combination of 1.0 μmol verapamil with 10 μmol quinine increased accumulation and retention of anthracycline in the resistant cells to a greater extent than did either drug individually (P < .001) and inhibited drug efflux as effectively as verapamil alone at 10 μmol. Our findings suggest that combined chemosensitization with verapamil and quinine may prove useful for overcoming MDR1 in patients with drug-refractory B-cell neoplasms such as multiple myeloma or non-Hodgkin's lymphomas.

Original languageEnglish (US)
Pages (from-to)348-354
Number of pages7
JournalBlood
Volume77
Issue number2
StatePublished - Jan 15 1991

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Quinine
Multiple Drug Resistance
P-Glycoprotein
Verapamil
Cells
Cell Line
Vinblastine
Pharmaceutical Preparations
Doxorubicin
Oral Administration
Plasmas
Anthracyclines
Multiple Myeloma
Intravenous Infusions
Refractory materials
Non-Hodgkin's Lymphoma
Assays
B-Lymphocytes

ASJC Scopus subject areas

  • Hematology

Cite this

Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model. / Lehnert, Manfred; Dalton, William S.; Roe, Denise; Emerson, Scott; Salmon, Sydney E.

In: Blood, Vol. 77, No. 2, 15.01.1991, p. 348-354.

Research output: Contribution to journalArticle

Lehnert, Manfred ; Dalton, William S. ; Roe, Denise ; Emerson, Scott ; Salmon, Sydney E. / Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model. In: Blood. 1991 ; Vol. 77, No. 2. pp. 348-354.
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