Sikic B I
General Clinical Research Center, Stanford University, CA 94305, USA.
Semin Hematol. 1997 Oct;34(4 Suppl 5):40-7.
The rationale for modulation of multidrug resistance (MDR) by inhibitors of the multidrug transporter, P-glycoprotein (P-gp) includes the following: (1) P-gp is expressed by human cancers, either at diagnosis or after failure of chemotherapy; (2) P-gp expression at diagnosis has been associated with a poor prognosis in some types of cancer; (3) MDR related to P-gp expression can be reversed by modulators, resulting in enhanced therapeutic efficacy in cellular and animal models of drug resistance; and (4) the emergence of MDR related to P-gp expression can be prevented in cellular models by co-administration of MDR-related cytotoxins and modulators. Clinical trials of modulation of MDR have been limited by two major factors: inability to achieve adequate levels of the modulators to reverse drug resistance in patients and the presence of other mechanisms of resistance in tumor cells in addition to P-gp. The former limitation will hopefully be overcome by new, more potent and specific inhibitors of P-gp such as PSC 833. The latter will require further understanding of various alternative cellular mechanisms of resistance and the development of approaches to overcome or circumvent these mechanisms. PSC 833 is associated with significant drug interactions with MDR-related cytotoxic agents, which require dose reduction of the cytotoxins to achieve a dose exposure and toxicity similar to the chemotherapy agents without a modulator. These drug interactions are predictable and are at least in part due to inhibition of P-gp in normal tissues such as the liver and kidneys, where P-gp is known to play a role in drug excretion. Data from knockout mice, which lack P-gp expression, support the concept that P-gp is an important factor in MDR-related drug disposition. Early data from phase I and II trials with PSC 833 indicate that substantial inhibition of P-gp can be achieved in patients at clinically tolerable doses of both modulator and cytotoxins. The ultimate therapeutic benefit of MDR modulation with PSC 833 is currently being tested in phase III clinical trials in acute myeloid leukemias (AMLs) and multiple myeloma.
通过多药转运蛋白P-糖蛋白（P-gp）抑制剂调节多药耐药性（MDR）的基本原理如下：（1）人类癌症在诊断时或化疗失败后会表达P-gp；（2）诊断时P-gp的表达与某些类型癌症的不良预后相关；（3）与P-gp表达相关的MDR可被调节剂逆转，从而在耐药性的细胞和动物模型中提高治疗效果；（4）在细胞模型中，通过联合使用与MDR相关的细胞毒素和调节剂，可以预防与P-gp表达相关的MDR的出现。MDR调节的临床试验受到两个主要因素的限制：无法在患者体内达到足够水平的调节剂以逆转耐药性，以及肿瘤细胞中除P-gp外还存在其他耐药机制。前一个限制有望通过新型、更有效且特异性更强的P-gp抑制剂（如PSC 833）来克服。后一个限制则需要进一步了解各种替代的细胞耐药机制，并开发克服或规避这些机制的方法。PSC 833与MDR相关的细胞毒性药物存在显著的药物相互作用，这需要降低细胞毒素的剂量，以达到与未使用调节剂的化疗药物相似的剂量暴露和毒性。这些药物相互作用是可预测的，至少部分是由于肝脏和肾脏等正常组织中P-gp的抑制，已知P-gp在这些组织的药物排泄中起作用。来自缺乏P-gp表达的基因敲除小鼠的数据支持了P-gp是MDR相关药物处置中一个重要因素的概念。PSC 833的I期和II期试验的早期数据表明，在临床可耐受的调节剂和细胞毒素剂量下，患者体内的P-gp可被大幅抑制。目前，PSC 833调节MDR的最终治疗益处正在急性髓性白血病（AML）和多发性骨髓瘤的III期临床试验中进行测试。
