Wise L David, Spence Stan, Saldutti Louise P, Kerr Janet S
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Birth Defects Res B Dev Reprod Toxicol. 2008 Feb;83(1):19-26. doi: 10.1002/bdrb.20139.
Histone deacetylase (HDAC) inhibitors have been shown to mediate the regulation of gene expression, induce cell growth, cell differentiation, and apoptosis of tumor cells. These compounds are now marketed or are in clinical development. One such HDAC inhibitor, vorinostat (suberoylanilide hydroxamic acid [SAHA], Zolinza), was assessed for its potential effects on fertility in Sprague-Dawley rats.
Female rats were administered oral dose levels of 0 (vehicle only), 15, 50, or 150 mg/kg/day of vorinostat for 14 days before cohabitation, during cohabitation, and through Gestation Day (GD) 7. In a separate study, male rats were administered oral dose levels of 0 (vehicle only), 20, 50, or 150 mg/kg/day for 10 weeks before cohabitation, during cohabitation, and until the day before scheduled sacrifice (approximately 14 weeks total). In both studies, % peri-implantation loss and % postimplantation loss were evaluated on GD 15-17. Testicular weight and histomorphology, cauda epididymal sperm count, and sperm motility were evaluated in the male rat study at termination.
There were treatment-related decreases in body weight gain at 150 mg/kg/day in both studies. There were no effects on mating or fertility indices in either study. In the female study there were increased numbers of corpora lutea in all drug-treated groups (only 1 or 2 affected dams in low and mid-dose groups), and a marked increase in percent postimplantation loss only in the high-dose group. No treatment-related effects were observed on litter or sperm parameters of the male study.
Vorinostat had no effects on mating or fertility in rats up to 150 mg/kg/day. There were no indications of reproductive toxicity in drug-treated male rats. Increases in corpora lutea or resorptions were observed in treated female rats.
组蛋白脱乙酰酶（HDAC）抑制剂已被证明可介导基因表达的调控，诱导肿瘤细胞的生长、分化和凋亡。这些化合物目前已上市或正处于临床开发阶段。其中一种HDAC抑制剂伏立诺他（辛二酰苯胺异羟肟酸[SAHA]，商品名Zolinza），已针对其对斯普拉格-道利大鼠生育能力的潜在影响进行了评估。
雌性大鼠在同居前、同居期间以及妊娠第7天（GD 7），口服给予0（仅赋形剂）、15、50或150 mg/kg/天的伏立诺他，持续14天。在另一项研究中，雄性大鼠在同居前、同居期间以及预定处死前一天（总共约14周），口服给予0（仅赋形剂）、20、50或150 mg/kg/天，持续10周。在两项研究中，均在GD 15 - 17评估着床前丢失率和着床后丢失率。在雄性大鼠研究结束时，评估睾丸重量和组织形态学、附睾尾部精子计数以及精子活力。
在两项研究中，150 mg/kg/天剂量组的体重增加均出现与治疗相关的下降。两项研究中对交配或生育指数均无影响。在雌性大鼠研究中，所有药物治疗组的黄体数量均增加（低剂量和中剂量组仅有1或2只受影响的母鼠），且仅高剂量组的着床后丢失率显著增加。在雄性大鼠研究中，未观察到与治疗相关的对窝仔数或精子参数的影响。
伏立诺他在高达150 mg/kg/天的剂量下对大鼠的交配或生育能力无影响。在接受药物治疗的雄性大鼠中未发现生殖毒性迹象。在接受治疗的雌性大鼠中观察到黄体数量增加或吸收现象。
