Graziano M J, Pilcher G D, Walsh K M, Kasali O B, Radulovic L
Department of Pathology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA.
Invest New Drugs. 1997;15(4):295-310. doi: 10.1023/a:1005937502511.
CI-994 (acetyldinaline) is an orally active anticancer drug currently in Phase 1 clinical trials. To assess its preclinical toxicity, CI-994 was administered orally as suspensions to Wistar rats (10/sex/dose) and in capsules to beagle dogs (3/sex/dose) once daily for two weeks. Doses were 1.5, 5, and 15 mg/kg for rats (9, 30, and 90 mg/m2, respectively), and 0.5, 2, and 5 mg/kg for dogs (10, 40, and 100 mg/m2, respectively). Systemic exposure was dose-proportional based on toxicokinetic analysis in dogs. Severe clinical signs and mortality occurred at the highest dose in both species beginning on Day 10. Neutropenia, lymphocytopenia, thrombocytopenia, lymphoid depletion, bone marrow hypocellularity, and testicular degeneration were observed in both species, primarily at the mid- and high-doses. Despite continued treatment, neutrophil counts in dogs returned to control levels in Week 2. Other microscopic findings in rats included splenic hematopoietic depletion at all doses and epithelial cell necrosis in various tissues at 15 mg/kg. Additional bone marrow changes in dogs involved myeloid and megakaryocyte hyperplasia at 2 mg/kg and abnormal myeloid and megakaryocyte maturation at 2 and 5 mg/kg. Except for the testicular effects in both species, all changes were reversible within a 4-week (rat) or 9-week (dog) recovery period. The results of these studies show that target organ effects of CI-994 principally involve tissues with rapidly dividing cell populations and that bone marrow suppression is the dose-limiting toxicity. CI-994 also seems to interfere with the release and/or maturation of cells in the bone marrow.
CI-994（乙酰二苯胺）是一种口服活性抗癌药物，目前正处于1期临床试验阶段。为评估其临床前毒性，将CI-994以混悬液形式口服给予Wistar大鼠（每组10只，雌雄各半），以胶囊形式口服给予比格犬（每组3只，雌雄各半），每日1次，持续2周。大鼠的剂量分别为1.5、5和15 mg/kg（分别相当于9、30和90 mg/m²），犬的剂量分别为0.5、2和5 mg/kg（分别相当于10、40和100 mg/m²）。基于对犬的毒代动力学分析，全身暴露呈剂量比例关系。从第10天开始，两个物种在最高剂量组均出现严重的临床症状和死亡。两个物种均观察到中性粒细胞减少、淋巴细胞减少、血小板减少、淋巴组织耗竭、骨髓细胞减少和睾丸变性，主要发生在中高剂量组。尽管持续给药，但犬的中性粒细胞计数在第2周恢复到对照水平。大鼠的其他微观发现包括各剂量组均出现脾造血功能减退，15 mg/kg剂量组各组织出现上皮细胞坏死。犬的骨髓其他变化包括2 mg/kg剂量组出现髓系和巨核细胞增生，2和5 mg/kg剂量组出现髓系和巨核细胞成熟异常。除两个物种均出现的睾丸效应外，所有变化在4周（大鼠）或9周（犬）的恢复期内均可逆转。这些研究结果表明，CI-994的靶器官效应主要累及细胞增殖迅速的组织，骨髓抑制是剂量限制性毒性。CI-994似乎还干扰骨髓中细胞的释放和/或成熟。
