Goldstein L J
Fox Chase Cancer Center, Department of Medical Oncology, Philadelphia, Pennsylvania, USA.
Curr Probl Cancer. 1995 Mar-Apr;19(2):65-124.
Although combination chemotherapy has had a significant impact on survival for malignancies such as Hodgkin's disease, testicular cancer, and childhood acute leukemias, the majority of cancers are either initially resistant to chemotherapy (renal, colon, etc.) or are initially chemosensitive but acquire resistance during treatment, such as lymphoma and breast cancer. Resistance to chemotherapy remains an obstacle to the successful treatment of human cancer and has been the subject of numerous investigations aimed at identifying the molecular mechanisms of resistance in cancer cells. An improved understanding of the mechanisms by which tumor cells develop resistance to chemotherapy may not only enhance the activity of cytotoxic therapy in advanced malignancies but may ultimately improve the impact of adjuvant therapy, potentially resulting in prolonging disease-free intervals and survival. In this review, therefore, we discuss our current understanding of the MDR1 gene, encoding P-glycoprotein, which is responsible for one mechanism of multidrug resistance (MDR). We also review the evidence supporting the clinical relevance of the MDR1 gene and clinical trials aimed at reversing MDR-mediated resistance. Although MDR-mediated drug resistance has been well characterized in preclinical models, its role in clinical drug resistance is not as well characterized and requires further investigation. Prospective studies are necessary to establish the role of MDR1 gene expression in the clinical resistance. The ability to identify tumors with increased MDR1 gene expression has several potential applications (for example, the prediction of response to chemotherapy and the design of studies aimed at reversal of resistance with agents that inhibit MDR-mediated drug efflux). The initial goal of such trials is to demonstrate the ability to reverse MDR1-mediated drug resistance in the appropriate advanced refractory malignancies. Ultimately, it will be important to incorporate these reversal strategies in the treatment of early-stage disease, at which time the tumor burden is smaller and fewer mechanisms of resistance may be present. Prospective phase I, II, and III clinical trials using reversing agents in conjunction with chemotherapy in malignancies that express the MDR1 gene, such as the hematologic malignancies and breast cancer, are necessary before routine use of agents such as verapamil, quinidine, and cyclosporine, which carry innate toxicities. MDR is a mechanism of drug resistance that provides the potential for an alteration in drug efflux, which may have a significant impact on response and possibly result in improved survival for some cancer patients.
尽管联合化疗对霍奇金病、睾丸癌和儿童急性白血病等恶性肿瘤的生存率产生了重大影响，但大多数癌症要么最初对化疗耐药（肾癌、结肠癌等），要么最初对化疗敏感但在治疗过程中产生耐药性，如淋巴瘤和乳腺癌。化疗耐药仍然是人类癌症成功治疗的障碍，并且一直是众多旨在确定癌细胞耐药分子机制的研究主题。更好地理解肿瘤细胞对化疗产生耐药性的机制，不仅可能增强晚期恶性肿瘤细胞毒性疗法的活性，而且最终可能改善辅助治疗的效果，有可能延长无病生存期和生存期。因此，在本综述中，我们讨论了目前对编码P-糖蛋白的MDR1基因的理解，该基因是多药耐药（MDR）的一种机制。我们还回顾了支持MDR1基因临床相关性的证据以及旨在逆转MDR介导的耐药性的临床试验。尽管MDR介导的耐药性在临床前模型中已得到充分表征，但其在临床耐药中的作用尚未得到充分表征，需要进一步研究。前瞻性研究对于确定MDR1基因表达在临床耐药中的作用是必要的。识别MDR1基因表达增加的肿瘤的能力有几个潜在应用（例如，预测化疗反应以及设计旨在用抑制MDR介导的药物外排的药物逆转耐药性的研究）。此类试验的最初目标是证明在适当的晚期难治性恶性肿瘤中逆转MDR1介导的耐药性的能力。最终，将这些逆转策略纳入早期疾病的治疗中很重要，此时肿瘤负荷较小且可能存在的耐药机制较少。在常规使用维拉帕米、奎尼丁和环孢素等具有固有毒性的药物之前，有必要在表达MDR1基因的恶性肿瘤（如血液系统恶性肿瘤和乳腺癌）中进行前瞻性I期、II期和III期临床试验，将逆转剂与化疗联合使用。MDR是一种耐药机制，它提供了药物外排改变的可能性，这可能对反应产生重大影响，并可能使一些癌症患者的生存期得到改善。
