TY - JOUR
T1 - Kinetic parameters for reversal of the multidrug pump as measured for drug accumulation and cell killing
AU - Lan, Lu Bin
AU - Ayesh, Suhail
AU - Lyubimov, Elena
AU - Pashinsky, Irina
AU - Stein, Wilfred D.
PY - 1996
Y1 - 1996
N2 - 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.
AB - 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.
KW - cell killing
KW - drug accumulation
KW - kinetics
KW - multidrug resistance
KW - reversal
UR - http://www.scopus.com/inward/record.url?scp=0029972620&partnerID=8YFLogxK
U2 - 10.1007/s002800050468
DO - 10.1007/s002800050468
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C2 - 8616910
AN - SCOPUS:0029972620
SN - 0344-5704
VL - 38
SP - 181
EP - 190
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -