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Drug Accumulation and Binding in P-Glycoprotein-Associated Multidrug Resistance

  • William T. Beck

Abstract

Multidrug resistance (MDR) is a complex phenomenon that has been well described in experimental systems (Beck, 1987; Pastan and Gottesman, 1987, 1988; Moscow and Cowan, 1988; Bradley et al., 1988; van der Bliek and Borst, 1989; Endicott and Ling, 1989). The characteristic feature, as detailed elsewhere in this volume, is a broad cross-resistance to a variety of apparently dissimilar natural-product compounds. The pharmacologic basis for MDR appears to be a decrease in the steady-state accumulation of drug, attributed to either its decreased uptake (Ling and Thompson, 1974) or decreased retention (Danø, 1973; Skovsgaard, 1978a). In turn, decreased drug retention has been ascribed either to increased activity of an “active efflux pump,” mediated through the action of a high-molecular-weight membrane glycoprotein, known as P-glycoprotein or to a diminished binding of drug (Beck, 1987, Pastan and Gottesman, 1988; Bradley et al., 1988; van der Bliek and Borst, 1989; Endicott and Ling, 1989). For clarity, I designate this form of MDR associated with overexpression of P-glycoprotein as Pgp-MDR, to distinguish it from another type of MDR associated with alterations in the essential nuclear enzyme, topoisomerase II, that we have termed at-MDR (Danks et al., 1987, 1988; Beck et al., 1987). Although decreased steady-state accumulation of drug distinguishes Pgp-MDR from other forms of MDR, the basis for this phenomenon has only recently begun to be understood.

Keywords

Drug Accumulation Drug Binding Vinca Alkaloid Human Leukemic Cell Human Leukemic Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Springer Science+Business Media New York 1991

Authors and Affiliations

  • William T. Beck
    • 1
  1. 1.Department of Biochemical and Clinical PharmacologySt. Jude Children’s Research HospitalMemphisUSA

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