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

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

Research output: Contribution to journalArticle

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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 (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 (TGFβ3) were assessed in fibroids using immunohistochemical analysis or RTPCR. 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 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.

Original languageEnglish (US)
Pages (from-to)3008-3018
Number of pages11
JournalHuman Reproduction
Volume26
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Guaiacol
Leiomyoma
Transferases
Poly Adenosine Diphosphate Ribose
Estrogens
Cyclin D1
In Situ Nick-End Labeling
Proliferating Cell Nuclear Antigen
Therapeutics
Apoptosis
Growth Inhibitors
Messenger RNA
DNA Nucleotidylexotransferase
Liver
Transforming Growth Factors
Ro 41-0960
Tumor Suppressor Genes
Osteoporosis
Extracellular Matrix
Histology

Keywords

  • catechol estrogen
  • catechol-O-methyl transferase inhibitor
  • Eker rats
  • estradiol
  • uterine leiomyomas

ASJC Scopus subject areas

  • Rehabilitation
  • Obstetrics and Gynecology
  • Reproductive Medicine

Cite this

Towards non-surgical therapy for uterine fibroids : Catechol-O-methyl transferase inhibitor shrinks uterine fibroid lesions in the Eker rat model. / Hassan, M. H.; Fouad, H.; Bahashwan, S.; Al-Hendy, A.

In: Human Reproduction, Vol. 26, No. 11, 01.11.2011, p. 3008-3018.

Research output: Contribution to journalArticle

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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 (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 (TGFβ3) were assessed in fibroids using immunohistochemical analysis or RTPCR. 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 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.",
keywords = "catechol estrogen, catechol-O-methyl transferase inhibitor, Eker rats, estradiol, uterine leiomyomas",
author = "Hassan, {M. H.} and H. Fouad and S. Bahashwan and A. Al-Hendy",
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T2 - Catechol-O-methyl transferase inhibitor shrinks uterine fibroid lesions in the Eker rat model

AU - Hassan, M. H.

AU - Fouad, H.

AU - Bahashwan, S.

AU - Al-Hendy, A.

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N2 - 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 (TGFβ3) were assessed in fibroids using immunohistochemical analysis or RTPCR. 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 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.

AB - 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 (TGFβ3) were assessed in fibroids using immunohistochemical analysis or RTPCR. 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 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.

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KW - catechol-O-methyl transferase inhibitor

KW - Eker rats

KW - estradiol

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