Early Vaginal Opening in Juvenile Female Rats Given BRAF-Inhibitor Dabrafenib Is Not Associated with Early Physiologic Sexual Maturation.

Autor: Posobiec LM; Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania., Vidal JD; Vet Path Services, Inc, Mason, Ohio., Hughes-Earle A; Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania., Laffan SB; Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania., Hart T; Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania.
Jazyk: angličtina
Zdroj: Birth defects research. Part B, Developmental and reproductive toxicology [Birth Defects Res B Dev Reprod Toxicol] 2015 Dec; Vol. 104 (6), pp. 244-52. Date of Electronic Publication: 2015 Dec 01.
DOI: 10.1002/bdrb.21165
Abstrakt: Dabrafenib (DAB), an inhibitor of BRAF kinase activity, is approved for metastatic melanoma with a BRAF V600E mutation. In support of pediatric cancer development, a nonclinical juvenile rat toxicity study was conducted in which females had early vaginal opening (VO). It was hypothesized that the early VO was not indicative of sexual maturation, but a result of a local effect on the vagina. An investigative study was conducted that mimicked the definitive study design, with rats given DAB or vehicle orally from Postnatal Day (PND) 7 to 35 and with necropsy subsets just before VO, at the first and second estrus, along with age-matched controls. Histopathology was performed on reproductive tissues, including immunohistochemistry for BRAF expression. VO occurred earlier in DAB females than in controls (PND 27.2 vs. 31.5); however, the timing of the first estrus was unaffected (PND 34.0 vs. 33.0). DAB-treated females evaluated just before VO (PND 22.0) had mostly immature reproductive tracts with no evidence of ovulation, similar to age-matched controls; however, DAB-treated females had keratinized and histologically open vaginas. Also, there was raised skin around the urogenital area, which correlated with hyperplasia/keratosis of the vulvar skin and keratinization of the distal vagina. BRAF expression (evaluated in controls) was localized to these tissues. Thus, early VO in rats given DAB likely represents a local effect accelerating vaginal keratinization to become open and not accelerated sexual maturation.
(© 2015 Wiley Periodicals, Inc.)
Databáze: MEDLINE