Kinetic parameters for reversal of the multidrug pump as measured for drug accumulation and cell killing

Lu Bin Lan, Suhail Ayesh, Elena Lyubimov, Irina Pashinsky, Wilfred D. Stein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the amplitude of the pertinent protocol (accumulation or cell killing), the K(i) for reversal of accumulation was generally some four or five times larger than that for reduction of cytotoxicity. We showed that this was only an apparent discrepancy, since a full theoretical analysis of the two protocols allowed the intrinsic K(i) to be obtained for the two procedures and these computed K(i) values were then almost identical. We found that for six of the modulators studied (namely, cyclosporin A, quinidine, dipyridamole, propafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature.

Original languageEnglish
Pages (from-to)181-190
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume38
Issue number2
DOIs
StatePublished - 1996

Keywords

  • cell killing
  • drug accumulation
  • kinetics
  • multidrug resistance
  • reversal

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