Cisplatin nephrotoxicity: molecular mechanisms.
Cisplatin nephrotoxicity: molecular mechanisms.
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发表时间：
2003
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通讯作者：
M. Hanigan;P. Devarajan
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文献类型：
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作者：
M. Hanigan;P. Devarajan
顺铂是治疗多种人类恶性肿瘤最广泛使用的化疗药物之一。顺铂的疗效是剂量依赖性的，但是肾毒性的显著风险经常阻碍使用更高剂量以最大化其抗肿瘤作用。顺铂肾毒性的生化和分子机制的理解的几个进展，最近出现，并在这篇文章中进行了审查。有证据表明，顺铂在活跃分裂的肿瘤细胞与正常静止的肾近端肾小管上皮细胞中的毒性机制不同。γ-谷氨酰转肽酶在顺铂肾毒性中的意外作用被阐明。最近的研究表明，近端肾小管细胞代谢顺铂的肾毒素的能力进行了审查。细胞凋亡作为顺铂诱导的肾细胞损伤的主要机制的证据，沿着的数据探索特定的细胞内途径，可能介导的程序性细胞死亡的作用。从这次审查中收集的信息可能会提供关键的线索，新的治疗干预措施，旨在尽量减少顺铂诱导的肾毒性，同时提高其疗效。
Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of several human malignancies. The efficacy of cisplatin is dose dependent, but the significant risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. Several advances in our understanding of the biochemical and molecular mechanisms underlying cisplatin nephrotoxicity have recently emerged, and are reviewed in this article. Evidence is presented for distinct mechanisms of cisplatin toxicity in actively dividing tumor cells versus the normally quiescent renal proximal tubular epithelial cells. The unexpected role of gamma-glutamyl transpeptidase in cisplatin nephrotoxicity is elucidated. Recent studies demonstrating the ability of proximal tubular cells to metabolize cisplatin to a nephrotoxin are reviewed. The evidence for apoptosis as a major mechanism underlying cisplatin-induced renal cell injury is presented, along with the data exploring the role of specific intracellular pathways that may mediate the programmed cell death. The information gleaned from this review may provide critical clues to novel therapeutic interventions aimed at minimizing cisplatin-induced nephrotoxicity while enhancing its antineoplastic efficacy.