Ribonucleotide reductase inhibitors: a new look at an old target for radiosensitization.
Ribonucleotide reductase inhibitors: a new look at an old target for radiosensitization.
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DOI：
10.3389/fonc.2011.00056
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发表时间：
2011
影响因子：
4.7
通讯作者：
Kinsella TJ
中科院分区：
文献类型：
--
作者：
Chapman TR;Kinsella TJ
核糖核苷酸还原酶（RR）是DNA合成和修复的限速酶，多年来一直被研究为癌症治疗中的抑制靶点。虽然一些研究人员已经将RR抑制剂作为化疗药物，特别是在血液恶性肿瘤中，但在放射增敏领域已经产生了一些最有希望的数据。早期的临床前研究表明，将这些药物中的第一种药物--这些研究，主要是在宫颈癌，最初产生了很大的兴趣，导致在许多机构的治疗方案中加入了羟基脲。然而，随着时间的推移，这些研究的结论受到质疑，在宫颈癌的标准治疗中，羟基脲已被取代。在过去的10年里，一些做得很好的临床前研究大大提高了我们对RR作为一个目标的理解。这些进展包括阐明p53 R2的作用，以及我们对IR的传递和RR的响应之间的时间关系的理解。与此同时，已经发现了具有增加的效力和改善的结合特性的新抑制剂，并且临床前和早期临床数据看起来很有希望。在这里，我们提出了一个全面的审查临床前和临床数据在该领域的日期，并提供了一些讨论未来的研究领域。
Ribonucleotide reductase (RR), the rate limiting enzyme in the synthesis and repair of DNA, has been studied as a target for inhibition in the treatment of cancer for many years. While some researchers have focused on RR inhibitors as chemotherapeutic agents, particularly in hematologic malignancies, some of the most promising data has been generated in the field of radiosensitization. Early pre-clinical studies demonstrated that the addition of the first of these drugs, hydroxyurea, to ionizing radiation (IR) produced a synergistic effect in vitro, leading to a large number of clinical studies in the 1970–1980s. These studies, mainly in cervical cancer, initially produced a great deal of interest, leading to the incorporation of hydroxyurea in the treatment protocols of many institutions. However, over time, the conclusions from these studies have been called into question and hydroxyurea has been replaced in the standard of care of cervical cancer. Over the last 10 years, a number of well-done pre-clinical studies have greatly advanced our understanding of RR as a target. Those advances include the elucidation of the role of p53R2 and our understanding of the temporal relationship between the delivery of IR and the response of RR. At the same time, new inhibitors with increased potency and improved binding characteristics have been discovered, and pre-clinical and early clinical data look promising. Here we present a comprehensive review of the pre-clinical and clinical data in the field to date and provide some discussion of future areas of research.