Friche E, Demant E J, Sehested M, Nissen N I
Department of Medicine and Hematology, Rigshospitalet-University Hospital, Copenhagen, Denmark.
Br J Cancer. 1993 Feb;67(2):226-31. doi: 10.1038/bjc.1993.44.
Eight anthracycline analogs that have been shown to modulate multidrug resistance (Friche et al., Biochem. Pharmacol., 39, 1721-1726; 1990) were tested for their inhibitory effect on the photolabelling of P-glycoprotein. We photoaffinity labelled P-glycoprotein in daunorubicin (DNR) resistant Ehrlich ascites tumour cells (EHR2/DNR +) with a [125I]iodinated Bolton-Hunter derivative of daunorubicin ([125I]iodomycin) and with [3H]azidopine. The photolabelling of P-glycoprotein by [125I]iodomycin was inhibited more than 50% by 10 microM (1000-fold molar excess) of DNR (52%), N,N-dibenzyl-DNR (52%), and N-benzyladriamycin-14-valerate (AD-198) (85%). Vincristine at 10 microM inhibited [125I]iodomycin labelling of P-glycoprotein by 95%. Thus vincristine was more potent than any of the eight anthracyclines tested, despite its relatively low lipophilicity. Increasing the concentration of DNR, AD-198 and N,N-dibenzyl-DNR to 40 microM resulted in 90, 99.5 and 99.5% inhibition of P-glycoprotein labelling by [125I]iodomycin, respectively. In comparison with the other anthracycline analogs, N,N-dibenzyl-DNR and Ad-198 were also found to exert the greatest inhibition of [3H]azidopine labelling of P-glycoprotein (about 90% at 100-fold molar excess). The solvents Cremophor EL and Tween 80 (30 micrograms ml-1; 0.003% v/v), which are modulators of multidrug resistance in EHR2/DNR + cells, also inhibited [125I]iodomycin labelling > 90%. We showed earlier that there is a correlation between the lipid solubility within the anthracycline group of MDR-associated drugs and their ability to enhance DNR accumulation in EHR2/DNR + cells but a corresponding correlation to lipophilicity when it comes to the inhibitory effect on the specific photolabelling of Pgp ligand binding sites could not be demonstrated. Neither could a correlation between the modulating effect of the analogs on DNR accumulation and inhibition on the labelling of Pgp be demonstrated. With increasing lipophilicity of the analogs it seems that the chemical structure plays a lesser role, and the degree of lipophilicity becomes a more important feature.
已证实可调节多药耐药性的8种蒽环类类似物（弗里切等人，《生物化学与药理学》，第39卷，第1721 - 1726页；1990年）被测试其对P - 糖蛋白光标记的抑制作用。我们用柔红霉素的[125I]碘化博尔顿 - 亨特衍生物（[125I]碘霉素）和[3H]叠氮平对柔红霉素（DNR）耐药的艾氏腹水瘤细胞（EHR2/DNR +）中的P - 糖蛋白进行光亲和标记。10 microM（1000倍摩尔过量）的DNR（52%）、N，N - 二苄基 - DNR（52%）和N - 苄基阿霉素 - 14 - 戊酸酯（AD - 198）（85%）使[125I]碘霉素对P - 糖蛋白的光标记抑制超过50%。10 microM的长春新碱对[125I]碘霉素标记P - 糖蛋白的抑制率为95%。因此，尽管长春新碱的亲脂性相对较低，但它比所测试的8种蒽环类药物中的任何一种都更有效。将DNR、AD - 198和N，N - 二苄基 - DNR的浓度增加到40 microM时，分别使[125I]碘霉素对P - 糖蛋白标记的抑制率达到90%、99.5%和99.5%。与其他蒽环类类似物相比，还发现N，N - 二苄基 - DNR和Ad - 198对[3H]叠氮平标记P - 糖蛋白的抑制作用最大（100倍摩尔过量时约为90%）。溶剂聚氧乙烯蓖麻油（Cremophor EL）和吐温80（30微克/毫升；0.003% v/v）是EHR2/DNR +细胞中多药耐药性的调节剂，它们对[125I]碘霉素标记的抑制率也> 90%。我们之前表明，多药耐药相关药物的蒽环类药物组内的脂溶性与其增强EHR2/DNR +细胞中DNR积累的能力之间存在相关性，但在对Pgp配体结合位点的特异性光标记的抑制作用方面，与亲脂性没有相应的相关性。类似物对DNR积累的调节作用与对Pgp标记的抑制作用之间也没有相关性。随着类似物亲脂性的增加，化学结构似乎起的作用较小，亲脂性程度成为更重要的特征。
