Reversal of acquired resistance to adriamycin in CHO cells by tamoxifen and 4-hydroxy tamoxifen: role of drug interaction with alpha 1 acid glycoprotein

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Abstract
Tamoxifen and 4-OH tamoxifen were used to reverse multidrug resistance (MDR) in CHO cells with acquired resistance to adriamycin (CHO-Adrr). Because alpha 1 acid glycoprotein (AAG) can bind a range of calcium channel blockers that also reverse MDR and rises in malignancy, its interactions with tamoxifen and 4-OH tamoxifen were also studied. Tamoxifen decreased the IC50 of 10 microM adriamycin 4.8-fold in the parent CHO-K1 cell line and 16-fold in CHO-Adrr. Similarly 4-OH tamoxifen decreased the IC50 3-fold in the parent cells, but 13-fold in the resistant cells. Tamoxifen and 4-OH tamoxifen were similarly potent in reversing MDR, although their anti-oestrogen potency differs 100-fold. AAG was added in increasing concentrations to the combination of adriamycin and tamoxifen. As AAG concentrations increased from 0.5 to 2 mg ml-1 (the range found in vivo) the effect of tamoxifen on reversing MDR was gradually decreased. At the highest AAG concentrations, there was complete reversal of the effects of both tamoxifen and 4-OH tamoxifen. AAG was found to bind 3H-tamoxifen in a non-saturable non-specific manner, in contrast to the binding of tamoxifen to albumin. Thus the use of tamoxifen as a reversal agent for MDR in vivo may be impaired by high binding to AAG. However, at the lower range of normal values of AAG, there was still an effect of 10 microM tamoxifen. It may be desirable to select patients for modifier studies based on AAG plasma levels.