BACKGROUND<\/p>\n
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<\/I>-methyl transferase inhibitor (COMTI), in the Eker rat.<\/p>\n
METHODS<\/p>\n
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<\/SUB>), 16-hydroxy E2 and DPD (osteoporosis marker) and serum liver enzymes were evaluated. Expressions of Cyclin D1<\/I>, proliferating cell nuclear antigen (PCNA<\/I>), Poly [ADP-ribose] polymerase1 (PARP1<\/I>), tumor suppressor gene (P53<\/I>) and transforming growth factor (TGFβ3<\/I>) were assessed in fibroids using immunohistochemical analysis or RT–PCR. Apoptosis was confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL).<\/p>\n RESULTS<\/p>\n 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<\/I>< 0.01). Ro 41-0960 increased the urinary 2-hydroxy E2\/16-hydroxy E2<\/SUB> ratio, level of p53<\/I> mRNA and TUNEL positivity (P<\/I>< 0.05) and decreased PARP1<\/I>, PCNA<\/I> and cyclin D1<\/I> proteins and TGFβ3<\/I> mRNA (P<\/I>< 0.05). Ro 41-0960 did not change normal tissue histology, liver functions or urinary DPD level.<\/p>\n CONCLUSIONS<\/p>\n 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.<\/p>\n Source: 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 … Continue reading
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