Lack of hydroxyurea-associated mutagenesis in pediatric sickle cell disease patients.
Lack of hydroxyurea-associated mutagenesis in pediatric sickle cell disease patients.
复制标题
儿童镰状细胞病患者缺乏羟基脲相关诱变。
DOI：
10.1002/em.22536
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发表时间：
2023
影响因子：
2.8
通讯作者：
Dertinger,StephenD
中科院分区：
文献类型：
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作者：
Torous,DorotheaK;Avlasevich,Svetlana;Bemis,JeffreyC;Howard,Thad;Ware,RussellE;Fung,Chunkit;Chen,Yuhchyau;Sahsrabudhe,Deepak;MacGregor,JamesT;Dertinger,StephenD
羟基脲被批准用于治疗儿童和成人镰状细胞性贫血（SCA）。尽管其功效已被证实，但对其致突变和致癌潜力的担忧仍然存在，这阻碍了其广泛使用。基于细胞培养和动物实验的研究表明，当超过高剂量和时间阈值时，羟基脲的遗传毒性作用是由于对特定细胞类型的间接致裂性（由Ware & Dertinger审查，2021年）。目前的研究将这些临床前观察扩展到接受羟基脲治疗SCA的儿科患者。首先，在接受顺铂治疗的睾丸癌患者中进行的原理验证实验验证了流式细胞术血液微核网状细胞（MN - RET）和猪突变网状细胞（MUT - RET）检测分别检测致裂性和基因突变的能力。其次，在一项横断面研究中，对26名接受羟基脲治疗的SCA患者和13名未暴露的SCA患者进行了这些生物标志物的测量。最后，在治疗6个月或12个月后，对10名SCA患者进行了一项前瞻性研究。暴露于顺铂的癌症患者在暴露数天内表现出MN‐RET的增加，而MUT RET终点需要更多的时间才能达到最高水平。在横断面和前瞻性研究中，在SCA患者中，羟基脲诱导MN - RET。然而，在羟基脲治疗的儿童中没有发现猪基因突变的证据，尽管这两种检测方法使用的是相同的快速分裂、高度暴露的细胞类型。总的来说，这些结果强化了MN‐RET和MUT RET生物标志物的互补性，并表明羟基脲在年轻SCA患者中可能具有致裂性，但不具有致突变性。
Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture‐ and animal‐based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof‐of‐principle experiments with testicular cancer patients exposed to a cisplatin‐based regimen validated the ability of flow cytometric blood‐based micronucleated reticulocyte (MN‐RET) andPIG‐Amutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross‐sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN‐RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN‐RET in both the cross‐sectional and prospective studies. However, no evidence ofPIG‐Agene mutation was found in hydroxyurea‐treated children, despite the fact that the two assays use the same rapidly‐dividing, highly‐exposed cell type. Collectively, these results reinforce the complementary nature of MN‐RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA.