Chan H S, DeBoer G, Haddad G, Gallie B L, Ling V
University of Toronto, Ontario, Canada.
Hematol Oncol Clin North Am. 1995 Apr;9(2):275-318.
Increased expression of P-glycoprotein is an important cause of multidrug resistance in tumor cell lines in vitro. Whether this mechanism is equally relevant as a cause of clinical chemoresistance has not been established and is currently being investigated. This review has examined the immunohistochemical and molecular biologic tools suitable for assessing P-glycoprotein expression in patient samples and methodologic issues important for evaluating the results of clinical studies. Current evidence that supports a role for P-glycoprotein in limiting the efficacy of cancer chemotherapy has been reviewed.
Malignancies that have been successfully treated by chemotherapeutic substrates of P-glycoprotein, in which a proportion of patients still fail therapy, may be the most useful models for determining whether this drug efflux transporter is a clinically relevant cause of chemoresistance.
Studies of acute myelogenous leukemia, lymphoma, and myeloma in adults have so far provided the best evidence for a relevant role for P-glycoprotein as a cause of clinical multidrug resistance. A similar strong association has been observed between the expression of P-glycoprotein and outcome of treatment in certain malignancies in children, such as neuroblastoma, rhabdomyosarcoma, and acute lymphoblastic leukemia. Some apparent controversies related to this issue of clinical relevance may be explained by the differences in P-glycoprotein detection techniques, methodology, and experimental designs used in different studies. Because several clinical trials have already been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy in certain malignancies, the successful verification of multidrug resistance limiting the cure rates of these tumors becomes a more critical issue, and identification of those patients with lower levels of P-glycoprotein expression early in the course of their disease, when they are most likely to benefit from multidrug resistance reversal, has assumed an even greater relevance.
The clinical relevance of the multidrug resistance P-glycoprotein may ultimately be confirmed by the successful prevention of chemotherapy failure by chemosensitizers that specifically reverse this drug efflux mechanism.
P-糖蛋白表达增加是体外肿瘤细胞系多药耐药的重要原因。该机制作为临床化疗耐药的原因是否同样相关尚未明确，目前正在研究中。本综述探讨了适用于评估患者样本中P-糖蛋白表达的免疫组织化学和分子生物学工具，以及对评估临床研究结果很重要的方法学问题。综述了支持P-糖蛋白在限制癌症化疗疗效中起作用的现有证据。
用P-糖蛋白的化疗底物成功治疗但仍有部分患者治疗失败的恶性肿瘤，可能是确定这种药物外排转运蛋白是否为临床相关化疗耐药原因的最有用模型。
迄今为止，对成人急性髓性白血病、淋巴瘤和骨髓瘤的研究为P-糖蛋白作为临床多药耐药原因的相关作用提供了最佳证据。在儿童的某些恶性肿瘤中，如神经母细胞瘤、横纹肌肉瘤和急性淋巴细胞白血病，也观察到P-糖蛋白表达与治疗结果之间有类似的强关联。不同研究中P-糖蛋白检测技术、方法和实验设计的差异，可能解释了与该临床相关性问题相关的一些明显争议。由于已经启动了多项临床试验来确定药物化学增敏是否能改善某些恶性肿瘤的化疗结果，成功验证多药耐药限制这些肿瘤治愈率成为一个更关键的问题，在疾病早期识别P-糖蛋白表达水平较低的患者，此时他们最有可能从多药耐药逆转中获益，这一点变得更加重要。
多药耐药P-糖蛋白的临床相关性最终可能通过特异性逆转这种药物外排机制的化学增敏剂成功预防化疗失败来证实。
