title: Towards non-surgical therapy for uterine fibroids: catechol-O-methyl transferase inhibitor shrinks uterine fibroid lesions in the Eker rat model.
abstract: BACKGROUND
  Uterine leiomyomas (fibroids) are the most common pelvic tumors in women. We assessed the potential therapeutic utility of Ro 41-0960, a synthetic catechol-O-methyl transferase inhibitor (COMTI), in the Eker rat.
  
  
  METHODS
  We randomized uterine fibroid-bearing Eker rats for treatment with Ro 41-0960 (150 mg/kg/12 h) versus vehicle for 2 and 4 weeks. The fibroids were measured by caliper and subjected to histological evaluation. Urinary levels of 2-hydroxy estrogen (E(2)), 16-hydroxy E2 and DPD (osteoporosis marker) and serum liver enzymes were evaluated. Expressions of Cyclin D1, proliferating cell nuclear antigen (PCNA), Poly [ADP-ribose] polymerase1 (PARP1), tumor suppressor gene (P53) and transforming growth factor (TGFβ3) were assessed in fibroids using immunohistochemical analysis or RT-PCR. Apoptosis was confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL).
  
  
  RESULTS
  Ro 41-0960-treated rats exhibited fibroid volumes of 86 ± 7% and 105 ± 12% of initial burden, at 2 and 4 weeks post-treatment, respectively, significantly lower than control group (240 ± 15% and 300 ± 18%; P< 0.01). Ro 41-0960 increased the urinary 2-hydroxy E2/16-hydroxy E(2) ratio, level of p53 mRNA and TUNEL positivity (P< 0.05) and decreased PARP1, PCNA and cyclin D1 proteins and TGFβ3 mRNA (P< 0.05). Ro 41-0960 did not change normal tissue histology, liver functions or urinary DPD level.
  
  
  CONCLUSIONS
  Ro 41-0960 (COMTI) arrested growth/shrunk uterine fibroids in Eker rats. This result may be related to modulation of estrogen-dependent genes involved in apoptosis, proliferation and extracellular matrix deposition via accumulation of 2-hydroxy estrogen. The efficacy and safety of Ro 41-0960 in rats suggest its candidacy for treatment of uterine fibroids.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy,  Al-Azhar University, Cairo,  Egypt.
authors: M H
authors: MH
authors: Hassan
authors: H
authors: H
authors: Fouad
authors: S
authors: S
authors: Bahashwan
authors: A
authors: A
authors: Al-Hendy
mesh_terms: D000818:Animals; D017209:Apoptosis; D001577:Benzophenones / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004967:Estrogens / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling; D007889:Leiomyoma / Q000188:drug therapy*; D011897:Random Allocation; D051381:Rats; D014594:Uterine Neoplasms / Q000188:drug therapy
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004967:Estrogens; C071721:Ro 41-0960