TY - JOUR
T1 - Mutually co-operative interactions between modulators of p-glycoprotein
AU - Shao, You Ming
AU - Ayesh, Suhail
AU - Stein, Wilfred D.
PY - 1997/2/27
Y1 - 1997/2/27
N2 - We measured the effects of combinations of verapamil, vinblastine, mefloquine, and tamoxifen, all being modulators of the multidrug resistance pump, P-glycoprotein, on the accumulation of labelled daunomycin into multidrug-resistant -388 leukemia cells at 37°C. We found that, contrary to our initial expectations (based on Ayesh, Shao and Stein (1996) Biochim. Biophys. Acta 1316, 8), vinblastine, mefloquine, and tamoxifen all appeared to interact with one another synergistically, i.e. by the kinetics of a non-competitive interaction. A simple kinetic analysis showed that pairs of co-operating modulators can give apparent non-competitive behaviour, but refined kinetic analysis enables the two types of interaction to be distinguished. The modulators vinblastine, mefloquine, and tamoxifen thus appear to co-operate with one another in pairs to bring about reversal of β-glycoprotein. This may have important implications for the design of new modulators of P-glycoprotein.
AB - We measured the effects of combinations of verapamil, vinblastine, mefloquine, and tamoxifen, all being modulators of the multidrug resistance pump, P-glycoprotein, on the accumulation of labelled daunomycin into multidrug-resistant -388 leukemia cells at 37°C. We found that, contrary to our initial expectations (based on Ayesh, Shao and Stein (1996) Biochim. Biophys. Acta 1316, 8), vinblastine, mefloquine, and tamoxifen all appeared to interact with one another synergistically, i.e. by the kinetics of a non-competitive interaction. A simple kinetic analysis showed that pairs of co-operating modulators can give apparent non-competitive behaviour, but refined kinetic analysis enables the two types of interaction to be distinguished. The modulators vinblastine, mefloquine, and tamoxifen thus appear to co-operate with one another in pairs to bring about reversal of β-glycoprotein. This may have important implications for the design of new modulators of P-glycoprotein.
KW - Behavior, non-competitive
KW - Cooperativity
KW - Kinetics
KW - Modulator
KW - Multidrug resistance
KW - P-glycoprotein
UR - http://www.scopus.com/inward/record.url?scp=0031049609&partnerID=8YFLogxK
U2 - 10.1016/S0925-4439(96)00065-8
DO - 10.1016/S0925-4439(96)00065-8
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C2 - 9061037
AN - SCOPUS:0031049609
SN - 0925-4439
VL - 1360
SP - 30
EP - 38
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 1
ER -