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首页> 外文期刊>International Journal of Environmental Research and Public Health >Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats
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Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats

机译：HZ1006的亚形毒性，基于羟胺的组蛋白脱乙酰酶抑制剂，在Beagle犬和Sprague-Dawley大鼠

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Histone deacetylase inhibitors (HDACIs), such as vorinostat and panobinostat, have been shown to have active effects on many hematologic malignancies, including multiple myeloma and cutaneous T-cell lymphoma. Hydroxamate-based (Hb) HDACIs have very good toxicity profiles and are currently being tested in phases I and II clinical trials with promising results in selected neoplasms, such as bladder carcinoma. One of the Hb-HDACIs, HZ1006, has been demonstrated to be a promising drug for clinical use. The aim of our study was to determine the possible target of toxicity and to identify a non-toxic dose of HZ1006 for clinical use. In our studies, the repeated dosage toxicity of HZ1006 in Beagle dogs and Sprague Dawley (SD) rats was identified. Dogs and rats received HZ1006 orally (0–80 and 0–120 mg/kg/day, respectively) on a continuous daily dosing agenda for 28 days following a 14-day dosage-free period. HZ1006’s NOAEL (No Observed Adverse Effect Level) by daily oral administration for dogs and rats was 5 mg/kg and 60 mg/kg, respectively, and the minimum toxic dose was 20 and 120 mg/kg, respectively. All the side effects indicated that the digestive tract, the male reproductive tract, the respiratory tract and the hematological systems might be HZ1006 toxic targets in humans. HZ1006 could be a good candidate or a safe succedaneum to other existing HDACIs for the treatment of some solid tumor and hematologic malignancies.
机译：已显示组蛋白脱乙酰酶抑制剂（如vorinostat和Panobinostat），如Vorinostat和Panobinostat，对许多血液学恶性肿瘤有活跃的影响，包括多种骨髓瘤和皮肤T细胞淋巴瘤。基于羟肟酸的（HB）HDACIS具有非常好的毒性谱，目前正在阶段进行测试，并且在临床试验中具有有前途的肿瘤，例如膀胱癌等临床试验。已经证明了HB-HDACIS HZ1006的一种用于临床使用的有希望的药物。我们研究的目的是确定毒性可能的靶点，并鉴定临床使用的HZ1006的无毒剂量。在我们的研究中，鉴定了Beagle犬和Spague Dawley（SD）大鼠HZ1006的重复剂量毒性。狗和大鼠在14天的无剂量期后连续每日给药议程，在连续的每日给药议程上，在连续的每日给药议程上接受HZ1006（0-80和0-120 mg / kg /天。每日口服对犬和大鼠的NOAEL（无观察到的不利影响水平）分别为5mg / kg和60mg / kg，最小毒性剂量分别为20〜120mg / kg。所有副作用表明消化道，雄性生殖道，呼吸道和血液学系统可能是人类的HZ1006毒性靶标。 HZ1006可以是对其他现有HDACIS的良好候选或安全的成功，用于治疗一些实体肿瘤和血液学恶性肿瘤。

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