title: Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats.
abstract: 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.
authors.affiliation: Center for Evaluation of Drug Safety, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China. haidaofang1980@163.com.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Evaluation of Drug Safety, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China. xiaodongzhang@163.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Evaluation of Drug Safety, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China. ybj74386@aliyun.com.
authors.forename: Bojun
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Center for Evaluation of Drug Safety, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China. renlijun@163.com.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ren
authors.affiliation: Center for Evaluation of Drug Safety, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China. tianbaozhang@163.com.
authors.forename: Tianbao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Center for Evaluation of Drug Safety, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China. guocailu1@163.com.
authors.forename: Guocai
authors.initials: G
authors.lastname: Lu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D001853:Bone Marrow / Q000187:drug effects; D002934:Cinnamates / Q000493:pharmacokinetics / Q000633:toxicity*; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005837:Genitalia, Male / Q000187:drug effects; D006400:Hematocrit; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D008168:Lung / Q000187:drug effects; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D059550:Toxicity Tests, Subchronic
chemical_list: D002934:Cinnamates; C000621550:HZ1006; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids
keywords: HZ1006; Hb-HDACIs; NOAEL; safety assessment