Mannargudi Mukundan Baskar, Deb Subrata
Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA.
Department of Biopharmaceutical Sciences, Roosevelt University College of Pharmacy, 1400 N. Roosevelt Blvd., Schaumburg, IL, 60173, USA.
J Cancer Res Clin Oncol. 2017 Aug;143(8):1499-1529. doi: 10.1007/s00432-017-2457-8. Epub 2017 Jun 17.
Ribonucleotide reductase (RR) enzymes (RR1 and RR2) play an important role in the reduction of ribonucleotides to deoxyribonucleotides which is involved in DNA replication and repair. Augmented RR activity has been ascribed to uncontrolled cell growth and tumorigenic transformation.
This review mainly focuses on several biological and chemical RR inhibitors (e.g., siRNA, GTI-2040, GTI-2501, triapine, gemcitabine, and clofarabine) that have been evaluated in clinical trials with promising anticancer activity from 1960's till 2016. A summary on whether their monotherapy or combination is still effective for further use is discussed.
Among the RR2 inhibitors evaluated, GTI-2040, siRNA, gallium nitrate and didox were more efficacious as a monotherapy, whereas triapine was found to be more efficacious as combination agent. Hydroxyurea is currently used more in combination therapy, even though it is efficacious as a monotherapy. Gallium nitrate showed mixed results in combination therapy, while the combination activity of didox is yet to be evaluated. RR1 inhibitors that have long been used in chemotherapy such as gemcitabine, cladribine, fludarabine and clofarabine are currently used mostly as a combination therapy, but are equally efficacious as a monotherapy, except tezacitabine which did not progress beyond phase I trials.
Based on the results of clinical trials, we conclude that RR inhibitors are viable treatment options, either as a monotherapy or as a combination in cancer chemotherapy. With the recent advances made in cancer biology, further development of RR inhibitors with improved efficacy and reduced toxicity is possible for treatment of variety of cancers.
核糖核苷酸还原酶（RR）（RR1和RR2）在核糖核苷酸还原为脱氧核糖核苷酸的过程中发挥重要作用，该过程参与DNA复制和修复。RR活性增强与细胞生长失控和肿瘤转化有关。
本综述主要聚焦于几种生物和化学RR抑制剂（如siRNA、GTI-2040、GTI-2501、曲阿普明、吉西他滨和氯法拉滨），这些抑制剂在1960年至2016年的临床试验中已被评估具有有前景的抗癌活性。讨论了关于它们单药治疗或联合治疗是否仍可有效用于进一步治疗的总结。
在评估的RR2抑制剂中，GTI-2040、siRNA、硝酸镓和双吗啉代乙烷单药治疗更有效，而曲阿普明作为联合用药更有效。羟基脲目前更多用于联合治疗，尽管它单药治疗也有效。硝酸镓在联合治疗中结果不一，而双吗啉代乙烷的联合活性尚未评估。长期用于化疗的RR1抑制剂如吉西他滨、克拉屈滨、氟达拉滨和氯法拉滨目前大多用作联合治疗，但单药治疗同样有效，除了替扎西他滨未超过I期试验。
基于临床试验结果，我们得出结论，RR抑制剂无论是单药治疗还是联合治疗，都是癌症化疗中可行的治疗选择。随着癌症生物学的最新进展，进一步开发疗效更好、毒性更低的RR抑制剂用于治疗多种癌症是可能的。
