Treatment for uterine fibroids: Searching for effective drug therapies

Taylor, Darlene K.; Leppert, Phyllis C.

doi:10.1016/j.ddstr.2012.06.001

Cited by 38 publications

(32 citation statements)

References 43 publications

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“…Our results support the efficacy of local GnRH-a therapy to inhibit ECM protein production despite the presence of gonadal hormones. Local drug delivery systems can include GnRH agonist-release intrauterine device (IUD) or more recent drug thermoresponsive delivery approach by smart nanocarriers (72). The use of such delivery devices may avoid the systemic side effects of direct injection of drug depot preparations.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones

Malik

Britten

Cox

et al. 2016

Fertility and Sterility

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This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy.

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Section: Discussionmentioning

confidence: 99%

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones

Malik

Britten

Cox

et al. 2016

Fertility and Sterility

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“…28 We observed a concentration-dependent significant reduction in COL-1A, FN1, versican, and FMOD proteins in 2D cultures of leiomyoma and myometrial cells. Given the highly disorganized nature of the leiomyoma collagen, 61 and the fact that mammalian collagenases degrade only specific bonds in the collagen molecule and do not degrade it completely, 67 it may be speculated that collagenases may not degrade all the collagen in a leiomyomata and a combination of different drugs may be required to treat uterine fibroids. 67 Collectively, our 2D data suggest that activation of the Rho/ROCK pathway is essential for ECM synthesis in uterine myometrium and leiomyoma cells and inhibition of the pathway might have therapeutic potential, as fasudil is associated with decreased matrix protein production as well as increase in signals for apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Leiomyoma Cells in 3-Dimensional Cultures Demonstrate an Attenuated Response to Fasudil, a Rho-Kinase Inhibitor, When Compared to 2-Dimensional Cultures

et al. 2014

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Uterine leiomyomata are common benign tumors in women of reproductive age and demonstrate an attenuated response to mechanical signaling that involves Rho and integrins. To further characterize the impairment in Rho signaling, we studied the effect of Rho-kinase inhibitor, fasudil, on extracellular matrix production, in 2-dimensional (2D) and 3-dimensional (3D) cultures of leiomyoma and myometrial cells. Leiomyoma 2D cultures demonstrated a rapid decrease in gene transcripts and protein for fibronectin, procollagen 1A, and versican. In 3D cultures, fibronectin and procollagen 1A proteins demonstrated increased levels at lower concentrations of fasudil, followed by a concentration-dependent decrease. Versican protein increased up to 3-fold, whereas fibromodulin demonstrated a significant decrease of 1.92-fold. Myometrial 2D or 3D cultures demonstrated a decrease in all proteins after 72 hours of treatment. The 3D leiomyoma cultures demonstrated a significant increase in active RhoA, followed by a concentration-dependent decrease at higher concentrations. A concentration-dependent increase in phosphoextracellular regulated signal kinase and proapoptotic protein Bax was observed in 3D leiomyoma cultures. Fasudil relaxed the contraction of the 3D collagen gels caused by myometrium and leiomyoma cell growth. These findings indicate that the altered state of Rho signaling in leiomyoma was more clearly observed in 3D cultures. The results also suggest that fasudil may have clinical applicability for treatment of uterine leiomyoma.

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“…The PFD is administered three times a day for a longer time to control chronic disease, such as IPF (Bruss et al, 2004). The clinical trial studies revealed several undesirable effects with oral administration of PFD including cough, head ache, diarrhea, fever, abnormality of hepatic function, dizziness and facial paralysis (King et al, 2014;Taylor & Leppert, 2012). Furthermore, PFD undergoes hepatic first-pass metabolism after oral administration (Arai et al, 2014).…”

Section: Introductionmentioning

confidence: 99%