Towards non-surgical therapy for uterine fibroids: catechol-O-methyl transferase inhibitor shrinks uterine fibroid lesions in the Eker rat model  

Oleh:

Hassan, M.H. ; Fouad, H. ; Bahashwan, S. ; Al-Hendy, A.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Human Reproduction vol. 26 no. 11 (Nov. 2011), page 3008-3018.
Topik: Uterine leiomyomas; catechol-O-methyl transferase inhibitor; Eker rats estradiol; catechol estrogen

Ketersediaan

Perpustakaan FK Nomor Panggil: H07.K.2011.02 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

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 (E2), 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 (TGFß3) 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 E2 ratio, level of p53 mRNA and TUNEL positivity (P< 0.05) and decreased PARP1, PCNA and cyclin D1 proteins and TGFß3 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.

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