RAD001 (Everolimus) Can prevent tamoxifen-related endometrial and stromal hyperplasia.
The mechanism of tamoxifen-associated endometrial hyperplasia and cancer is not elicited. RAD001 inhibits a target protein in phosphatidyl kinase pathway, which is involved in endometrial hyperplasia and cancer. We investigated whether endometrial hyperplasia can be prevented through inhibition of the target of rapamycin by RAD001. Sixty BALB/c mice underwent oophorectomy and were divided into 6 groups: group 1, placebo group; group 2, tamoxifen-treated (4 mg/kg per 24 hours); group 3, estradiol-treated (4 mg/kg per 24 hours); group 4, RAD001-treated (1.5 mg/kg per 24 hours); group 5, tamoxifen (4 mg/kg per 24 hours)-and-RAD001 (1.5 mg/kg per 24 hours)-treated; and group 6, estradiol (4 mg/kg per 24 hours)-and-RAD001 (1.5 mg/kg per 24 hours)-treated. The count of glands, the length of epithelium, and immunohistochemical staining of proliferating cell nuclear antigen were analyzed. The count of total glands and the epithelial length were 30.8 (7.1) and 126 (43.4) microm, 53 (8.1) and 162.5 (34.8) microm, 65.2 (13.6) and 401.4 (44.0) microm, and 82.0 (5.2) and 444.7 (57.8) microm in the placebo-, the RAD001-, the tamoxifen-, and the estradiol-treated groups, respectively (P < 0.05). Although addition of RAD001 to estradiol did not decrease the count of total glands and the epithelial length, addition of RAD001 to tamoxifen did (43.3 [13.3] and 218.0 [29.2] microm, P < 0.05). The immunoreactive score of proliferating cell nuclear antigen is significantly decreased by the addition of RAD001 to either tamoxifen or estradiol in the epithelial and glandular cells. RAD001 can prevent tamoxifen-associated and estrogen-related endometrial hyperplasias in mice. RAD001 also decreases stromal cell proliferation in the tamoxifen-treated mice.
Erdemoglu
Evrim
E
Department of Obstetrics and Gynecology, Süleyman Demirel University, Isparta, Turkey. erdemoglu@med.sdu.edu.tr
Güney
Mehmet
M
Take
Gülnur
G
Giray
Seren Gülşen
SG
Mungan
Tamer
T
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000517:prevention & control* / Q000601:surgery; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000517:prevention & control* / Q000601:surgery; D004958:Estradiol / Q000009:adverse effects; D004967:Estrogens / Q000009:adverse effects; D000068338:Everolimus; D005260:Female; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010052:Ovariectomy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000009:adverse effects*; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; D004967:Estrogens; D007166:Immunosuppressive Agents; D013629:Tamoxifen; D004958:Estradiol; D000068338:Everolimus; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus