Wernyj Roman P, Morin Patrice J
Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, MD 21224, USA.
Drug Resist Updat. 2004 Aug-Oct;7(4-5):227-32. doi: 10.1016/j.drup.2004.08.002.
The platinum compounds cisplatin and carboplatin are commonly used in cancer chemotherapy. However, tumors frequently develop resistance to these compounds, significantly decreasing their usefulness in the clinic. In the past few years, basic research has unraveled novel and unexpected mechanisms for the development of platinum resistance. For example, it has been reported that MUC1 expression and particularly the localization of its C-terminal subunit to the mitochondria may affect cisplatin resistance. Another recent finding suggests that cisplatin damage may activate DNA-dependent protein kinase (DNA-PK) to initiate a death signal that can be transmitted to neighboring cells through gap junctions, adding to a growing belief that the interactions of cancer cells with their surroundings may be important to the outcome of chemotherapy. While most clinical efforts have focused on identifying alternative regimens for drug-resistant cancer, it might be possible to exploit our knowledge of the mechanism of platinum resistance to specifically reverse resistance and increase platinum efficacy. The strategy of drug resistance reversal therapy (DRRT) may have significant impact on our approaches to the treatment and management of drug-resistant tumors.
铂类化合物顺铂和卡铂常用于癌症化疗。然而，肿瘤常常会对这些化合物产生耐药性，这显著降低了它们在临床上的效用。在过去几年中，基础研究揭示了铂耐药性产生的新的意外机制。例如，有报道称，MUC1的表达，尤其是其C末端亚基在线粒体中的定位，可能会影响顺铂耐药性。最近的另一项发现表明，顺铂损伤可能会激活DNA依赖性蛋白激酶（DNA-PK），从而启动一个死亡信号，该信号可通过间隙连接传递给邻近细胞，这进一步加深了人们的一种认识，即癌细胞与其周围环境的相互作用可能对化疗结果至关重要。虽然大多数临床努力都集中在为耐药癌症寻找替代治疗方案上，但利用我们对铂耐药机制的了解来特异性地逆转耐药性并提高铂类药物的疗效或许是可行的。耐药逆转治疗（DRRT）策略可能会对我们治疗和管理耐药肿瘤的方法产生重大影响。
