Assessment of female and male fertility in Sprague-Dawley rats administered vorinostat, a histone deacetylase inhibitor.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wise
L David
LD
Merck Research Laboratories, West Point, Pennsylvania 19486, USA. ld_wise@merck.com
Spence
Stan
S
Saldutti
Louise P
LP
Kerr
Janet S
JS
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005327:Fetal Resorption / Q000139:chemically induced; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat