Mechanism of action of hydroxyurea.
Mechanism of action of hydroxyurea.
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羟基脲的作用机制。
作者：
J. Yarbro
羟基脲口服后吸收良好，在体内转化为自由基硝基氧，并通过扩散转运至细胞内，猝灭核糖核苷酸还原酶M2蛋白亚基活性位点的酪氨酰自由基，使酶失活。包括核糖核苷酸还原酶在内的整个 replitase 复合物被灭活，DNA 合成被选择性抑制，导致 S 期细胞死亡和存活细胞部分的同步化。羟基脲也会抑制化学物质或辐射损伤的 DNA 修复，从而提供羟基脲与辐射或烷化剂之间的潜在协同作用。羟基脲使细胞对博莱霉素敏感，因为猝灭的酪氨酰自由基不再稳定邻近的铁中心，使其更容易受到博莱霉素的螯合特性的影响，然后博莱霉素会产生活性氧。羟基脲和许多其他化疗药物（包括阿糖胞苷和依托泊苷）之间也观察到了协同作用。最近，观察到羟基脲的两种新作用：羟基脲增加胎儿血红蛋白的水平，从而减少镰状细胞性贫血中血管闭塞危象的发生率；羟基脲选择性地降低游离DNA的水平，因此可能降低与作为游离体保留的重复基因相关的耐药性。有必要进一步探索羟基脲与其他治疗剂联合使用的功效。
Hydroxyurea is well absorbed after oral administration, converted to a free radical nitroxide in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replitase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea renders cells sensitive to bleomycin because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to the chelating properties of bleomycin, which then produces active oxygen. Synergy has also been observed between hydroxyurea and a number of other chemotherapeutic agents, including cytarabine and etoposide. Recently, two new effects of hydroxyurea have been observed: hydroxyurea increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia, and hydroxyurea selectively reduces the level of episomal DNA and thus potentially may reduce drug resistance associated with duplicated genes retained as episomes. Further exploration of the efficacy of hydroxyurea in combination with other therapeutic agents is warranted.
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3----5 外脱氧核糖核酸酶活性与来自 S 期中国仓鼠胚胎成纤维细胞的 DNA 复制酶复合物的关联。
影响因子：
3.7
作者：
Hammond,RA;Miller,MR;Gray,MS;Reddy,GP
通讯作者：
Reddy,GP
羟基脲耐药白血病 L1210 细胞的交叉耐药模式。
影响因子：
11.2
作者：
Carter,GL;Cory,JG
通讯作者：
Cory,JG
序贯羟基脲-阿糖胞苷化疗治疗难治性非霍奇金淋巴瘤。
DOI：
10.1200/jco.1987.5.3.419
发表时间：
1987
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Schilsky,RL;Williams,SF;Ultmann,JE;Watson,S
通讯作者：
Watson,S
羟基脲对体外胎儿血红蛋白产生的影响。
影响因子：
20.3
作者：
Miller,BA;Platt,O;Hope,S;Dover,G;Nathan,DG
通讯作者：
Nathan,DG
影响因子：
11.2
作者：
A. Sato;J. G. Cory
通讯作者：
A. Sato;J. G. Cory