Vergote J, Moretti J L, de Vries E G, Garnier-Suillerot A
Laboratoire de Physicochimie Biomoléculaire et Cellulaire, Université Paris Nord, Bobigny, France.
Eur J Biochem. 1998 Feb 15;252(1):140-6. doi: 10.1046/j.1432-1327.1998.2520140.x.
The overexpression of two membrane glycoproteins, P-glycoprotein and multidrug-resistance protein (MRP1) is a major cause of resistance to chemotherapeutic agents in the treatment of human cancers. Both proteins confer a similar multidrug-resistant (MDR) phenotype. 99mTc-MIBI, a myocardial imaging agent, which is also useful for the detection of a variety of tumours, has been shown to be a substrate for P-glycoprotein and MRP1. It thus may provide additional information about the P-glycoprotein and MRP1 status of tumour cells. In order to obtain information on the substrate specificity of these proteins, we have studied the transport kinetics of Tc-MIBI in two cell lines, K562/ADR and GLC4/ADR, which overexpress P-glycoprotein and MRP1, respectively. The mean active efflux coefficient ka, which is proportional to the ratio of maximal efflux rate VM to the apparent Michaelis-Menten constant Km, used to characterise the efficiency of the active efflux, was very similar being 1.9 +/- 0.6 x 10(-11) s(-1) x cells x ml and 1.3 +/- 0.5 x 10(-11) s(-1) x cells x ml for drug-resistant K562 and GLC4, respectively. These values are 50-100-times lower than for daunorubicin and other anthracycline derivatives, strongly suggesting that the efficiency of both transporters to pump Tc-MIBI is by far less than that to efflux anthracyclines. Our data show that (a) P-glycoprotein and MRP transporter efficiencies to wash out Tc-MIBI are similar, in spite of a different suspected mechanism of its transport and (b) that both transporters are less efficient to pump Tc-MIBI than to pump anthracyclines (the ka parameter is about 100-times lower for TC-MIBI than for anthracycline).
两种膜糖蛋白，即P-糖蛋白和多药耐药蛋白（MRP1）的过表达是人类癌症治疗中对化疗药物产生耐药性的主要原因。这两种蛋白都赋予相似的多药耐药（MDR）表型。99mTc-MIBI是一种心肌显像剂，也可用于检测多种肿瘤，已被证明是P-糖蛋白和MRP1的底物。因此，它可能提供有关肿瘤细胞P-糖蛋白和MRP1状态的额外信息。为了获得这些蛋白底物特异性的信息，我们研究了99mTc-MIBI在两种细胞系K562/ADR和GLC4/ADR中的转运动力学，这两种细胞系分别过表达P-糖蛋白和MRP1。平均主动外排系数ka与最大外排速率VM与表观米氏常数Km的比值成正比，用于表征主动外排效率，对于耐药的K562和GLC4细胞系，其值非常相似，分别为1.9±0.6×10⁻¹¹ s⁻¹×细胞×ml和1.3±0.5×10⁻¹¹ s⁻¹×细胞×ml。这些值比柔红霉素和其他蒽环类衍生物低50 - 100倍，强烈表明这两种转运蛋白泵出99mTc-MIBI的效率远低于泵出蒽环类药物的效率。我们的数据表明：（a）尽管P-糖蛋白和MRP转运蛋白对99mTc-MIBI的转运机制不同，但它们洗脱出99mTc-MIBI的效率相似；（b）这两种转运蛋白泵出99mTc-MIBI的效率低于泵出蒽环类药物的效率（99mTc-MIBI的ka参数比蒽环类药物低约100倍）。
