Schinkel A H, Mol C A, Wagenaar E, van Deemter L, Smit J J, Borst P
The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands.
Eur J Cancer. 1995 Jul-Aug;31A(7-8):1295-8. doi: 10.1016/0959-8049(95)00130-b.
Drug resistance, be it intrinsic or acquired, is a major problem in cancer chemotherapy. In vitro, one well characterised form of resistance against many different cytotoxic drugs is caused by the MDR1 P-glycoprotein, a large plasma membrane protein that protects the cell by actively pumping substrate drugs out. Available evidence suggests that this protein may cause drug resistance in at least some clinical tumours. Drugs inhibiting the MDR1 P-glycoprotein activity are, therefore, co-administered during chemotherapy of these tumours. To predict the biological and pharmacological effects of the blocking of this protein, we have generated mice with a genetic disruption of the drug-transporting mdr1a P-glycoprotein. These mice are overall healthy, but they accumulate much higher levels of substrate drugs in the brain, and have markedly slower elimination of these drugs from the circulation. For some drugs, this leads to dramatically increased toxicity, indicating that P-glycoprotein inhibitors should be used with caution in patients.
耐药性，无论是内在的还是后天获得的，都是癌症化疗中的一个主要问题。在体外，一种针对许多不同细胞毒性药物的特征明确的耐药形式是由MDR1 P-糖蛋白引起的，MDR1 P-糖蛋白是一种大型质膜蛋白，通过主动将底物药物泵出细胞来保护细胞。现有证据表明，这种蛋白可能在至少一些临床肿瘤中导致耐药性。因此，在这些肿瘤的化疗过程中会联合使用抑制MDR1 P-糖蛋白活性的药物。为了预测阻断这种蛋白的生物学和药理学效应，我们培育出了药物转运mdr1a P-糖蛋白基因缺失的小鼠。这些小鼠总体健康，但它们大脑中底物药物的积累水平要高得多，并且这些药物从循环中清除的速度明显较慢。对于某些药物，这会导致毒性大幅增加，这表明P-糖蛋白抑制剂在患者中应谨慎使用。
