Liu Fu-Shing
Department of Obstetrics and Gynecology, Show Chwan Memorial Hospital, Changhua, Taiwan.
Taiwan J Obstet Gynecol. 2009 Sep;48(3):239-44. doi: 10.1016/S1028-4559(09)60296-5.
Chemotherapy is one of the principal modes of treatment for cancer patients. Clinically, many tumors present a satisfactory response when they are first exposed to the chemotherapeutic drugs. However, drug resistance occurs sooner or later in these tumors, and the majority of the patients develop progressive disease. The mechanisms of treatment failure of chemotherapeutic drugs have been well studied. Via a unique protection system, i.e. multidrug resistance (MDR), the cancer cells can escape the toxic effect of most commonly used cancer drugs in spite of their different chemical structures and different mechanisms of intracellular activity. There are two classes of transporter proteins at the cellular surface which are responsible for MDR in tumors. One is the adenosine triphosphate-binding cassette transporter superfamily, which is an energy-requiring efflux pump with the function of extruding toxic chemotherapeutic drugs from the cancer cells. The other is the solute carrier transporter superfamily, which mediates the cellular uptake of anticancer drugs, and drug resistance may result from decreased activity of these transporters. Although transporters of MDR are responsible for the tumor resistance to many chemotherapeutic drugs currently used in cancer therapy, the mechanisms of resistance to platinum-based antitumor agents are through different pathways. In this article, the mechanisms of MDR transporters mediating resistance to the commonly used chemotherapeutic drugs and to platinum-based agents are reviewed. Finally, with the finding of cancer stem cells in more and more solid tumors, it is recognized that the cancer stem cell is spared along with its normal tissue stem cell counterparts with very subtle differences. One characteristic of the normal tissue stem cell is the self-protection ability through innate MDR transporters. Therefore, the essential self-protection property is also present in the cancer stem cells. The quiescent tumor stem cell with constitutive MDR is the main barrier to therapy. Successful cancer therapy will depend on the ability to discern the subtle differences between the tumor and normal stem cells so that approaches can be developed to eliminate the tumor stem cells without excessive toxicity to normal stem cells.
化疗是癌症患者主要的治疗方式之一。临床上，许多肿瘤在初次接触化疗药物时会呈现出令人满意的反应。然而，这些肿瘤迟早会出现耐药性，并且大多数患者会病情进展。化疗药物治疗失败的机制已得到充分研究。通过一种独特的保护系统，即多药耐药（MDR），癌细胞能够逃避大多数常用抗癌药物的毒性作用，尽管这些药物具有不同的化学结构和细胞内活性机制。肿瘤细胞表面有两类转运蛋白负责多药耐药。一类是三磷酸腺苷结合盒转运体超家族，它是一种需要能量的外排泵，具有将有毒化疗药物从癌细胞中排出的功能。另一类是溶质载体转运体超家族，它介导抗癌药物的细胞摄取，而耐药性可能是由于这些转运体活性降低所致。虽然多药耐药转运体导致肿瘤对目前癌症治疗中使用的许多化疗药物产生耐药性，但对铂类抗肿瘤药物的耐药机制是通过不同途径。本文综述了多药耐药转运体介导对常用化疗药物和铂类药物耐药的机制。最后，随着越来越多实体瘤中癌症干细胞的发现，人们认识到癌症干细胞与其正常组织干细胞对应物一起被保留，只是存在非常细微的差异。正常组织干细胞的一个特征是通过先天的多药耐药转运体具有自我保护能力。因此，癌症干细胞也具有这种基本的自我保护特性。具有组成型多药耐药的静止肿瘤干细胞是治疗的主要障碍。成功的癌症治疗将取决于能否辨别肿瘤干细胞与正常干细胞之间的细微差异，从而开发出既能消除肿瘤干细胞又不会对正常干细胞产生过度毒性的方法。
