Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.
Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.
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CD-1 小鼠中地西他滨与四氢尿苷联用的亚慢性口服毒性研究。
DOI：
10.1177/1091581814524994
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发表时间：
2014-03
影响因子：
2.2
通讯作者：
Covey JM
中科院分区：
文献类型：
--
作者：
Terse P;Engelke K;Chan K;Ling Y;Sharpnack D;Saunthararajah Y;Covey JM
地西他滨(5-氮-2‘-脱氧胞苷)联合四氢尿苷(清华)是治疗镰状细胞病和β-地中海贫血的潜在口服疗法。在小鼠身上进行了一项研究，以评估这种联合治疗的安全性，方法是在DAC前1小时口服清华和DAC，连续两天/周，最多9周，然后28天恢复，以支持其临床试验，最长9周。清华是胞苷脱氨酶的竞争性抑制剂，用于提高DAC的口服生物利用度。剂量为167 mg/kg清华+0、0.2、0.4或1.0 mg/kg DAC；清华合剂+1.0 mg/kg DAC；或单纯赋形剂。评估的终点是临床观察、体重、食物摄入量、临床病理、大体/组织病理学、骨髓微核和毒代动力学。在体重、食物消耗量、血清化学或尿检参数方面没有观察到与治疗相关的影响。在1小时内观察到血浆DAC水平的Cmax随剂量和性别的变化。在所测试的1 mg/kg剂量下，清华大学的DAC血浆浓度比单独使用DAC增加了约10倍。接受高剂量1 mg/kg DAC+清华的女性出现严重毒性，需要在第5周停止治疗。显微镜检查的严重程度和发生率随着剂量的增加而增加，表现为骨髓细胞减少(伴随相应的血液学变化；白细胞、红细胞、血红蛋白、红细胞压积、网织红细胞、中性粒细胞和淋巴细胞减少)，胸腺/淋巴组织耗竭，肠上皮细胞凋亡和睾丸变性。骨髓微核试验证实了骨髓细胞毒性、红细胞生成抑制和遗传毒性。在恢复期之后，观察到这些影响完全或有消除的趋势。总之，联合治疗导致对DAC毒性的敏感性增加，与DAC血浆水平相关，女性比男性更敏感。
Decitabine (5-aza-2’-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and β-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on two consecutive days/week for up to 9-weeks followed by a 28-day recovery to support its clinical trials upto 9 week duration. THU, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; or THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. Endpoints evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry or urinalysis parameters. Dose- and gender- dependent changes in plasma DAC levels were observed with a Cmax within 1 hr. At the 1mg/kg dose tested, THU increased DAC plasma concentration (~10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high dose 1mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes; decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoeisis, and genotoxicity. Following the recovery period, a complete or trend towards resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.
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影响因子：
12.8
作者：
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通讯作者：
DeSimone, Joseph
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