Lehne G, Rugstad H E
Department of Clinical Pharmacology, The National Hospital, Rikshospitalet, University of Oslo, Norway.
Br J Cancer. 1998 Sep;78(5):593-600. doi: 10.1038/bjc.1998.546.
Multidrug resistance (MDR) to anti-cancer agents is frequently associated with overexpression of the drug efflux transporter P-glycoprotein (Pgp) in cancer cells, ensuing drug expulsion and maintenance of tolerable intracellular levels of certain cytotoxic drugs. Pgp may also be present in normal tissue, providing protection against toxic substances, but the physiological role of Pgp is not fully understood. Recently, it was shown that Pgp also takes part in the transport of certain growth-regulating cytokines (Drach et al, 1996; Raghu et al, 1996). Therefore, we studied the effect of the highly potent Pgp inhibitor PSC 833 on proliferation of three pairs of MDR and parental human cell lines (HB8065 hepatoma cells, KG1a and K562 leukaemia cells). The MDR phenotypes were characterized by Pgp overexpression, which was demonstrated by flow cytometry using the anti-Pgp antibody MRK16. Electronic cell counting of 72-96 h cultures revealed a dose-dependent antiproliferative effect of PSC 833 in the resistant KG1a/200 and K562/150 cells. The half-maximal growth inhibitory concentrations (GI50) were 0.2 microM and 0.7 microM respectively. Exposure to PSC 833 induced cell death by apoptosis in both cell types, as revealed by flow cytometry and detection of 3'-hydroxy ends of DNA (the result of DNA fragmentation associated with apoptosis), by terminal transferase-mediated dUTP-biotin nick end-labelling (TUNEL). Similar effects were not found in the hepatoma cell lines or the parental leukaemia lines. These results demonstrated a discriminating cytotoxicity of PSC 833 in two human leukaemia MDR variants, representing a possible therapeutic indication which warrants consideration during the ongoing clinical evaluation of this drug.
对抗癌药物的多药耐药性（MDR）通常与癌细胞中药物外排转运体P-糖蛋白（Pgp）的过表达相关，从而导致药物排出并维持某些细胞毒性药物可耐受的细胞内水平。Pgp也可能存在于正常组织中，起到抵御有毒物质的作用，但Pgp的生理作用尚未完全明确。最近的研究表明，Pgp也参与某些生长调节细胞因子的转运（德拉赫等人，1996年；拉古等人，1996年）。因此，我们研究了高效Pgp抑制剂PSC 833对三对MDR和亲本人类细胞系（HB8065肝癌细胞、KG1a和K562白血病细胞）增殖的影响。通过使用抗Pgp抗体MRK16的流式细胞术证实，MDR表型的特征是Pgp过表达。对72 - 96小时培养物进行电子细胞计数，结果显示PSC 833对耐药的KG1a/200和K562/150细胞具有剂量依赖性的抗增殖作用。半数最大生长抑制浓度（GI50）分别为0.2微摩尔和0.7微摩尔。流式细胞术以及通过末端转移酶介导的dUTP-生物素缺口末端标记（TUNEL）检测DNA的3'-羟基末端（与凋亡相关的DNA片段化结果）显示，暴露于PSC 833会诱导这两种细胞类型发生凋亡性细胞死亡。在肝癌细胞系或亲代白血病细胞系中未发现类似效果。这些结果证明了PSC 833对两种人类白血病MDR变体具有特异性细胞毒性，这代表了一种可能的治疗指征，在该药物正在进行的临床评估中值得考虑。
