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Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium.

ABSTRACT: Uterine leiomyomas are highly prevalent and often symptomatic, but current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. The goal of these studies was to determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on leiomyoma cell proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947. In vitro progestational activity was assessed by alkaline phosphatase assay and ER-? expression. In vivo progestational activity was assayed by the McPhail assay. Proliferation and gene expression studies were performed in immortalized human leiomyoma and myometrial cells. Both CP8863 and CP8947 were highly selective for progesterone receptor (PR) but not for ER-?, AR, and GR. Both compounds induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-? in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium. Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. Extracellular matrix components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. CP8947 was a potent novel non-steroidal SPRM that was selective for PR, demonstrated progestational activity in endometrium, inhibited leiomyoma cell proliferation and decreased ECM component production, without disrupting myometrial cell proliferation.

SUBMITTER: Catherino WH

PROVIDER: S-EPMC3576019 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium.

Catherino William H WH Malik Minnie M Driggers Paul P Chappel Scott S Segars James J Davis Joseph J

The Journal of steroid biochemistry and molecular biology 20100520 4

Uterine leiomyomas are highly prevalent and often symptomatic, but current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. The goal of these studies was to determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on leiomyoma cell proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947. In vitro progestational act ...[more]

PMID: 20493256

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Project description:Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioidesdifficile disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibitor, was investigated. Dogs received amoxicillin (40 mg/kg, orally (PO), three times a day (TID)) or the combined antibiotic/beta-lactamase inhibitor, amoxicillin/clavulanate (40 mg/kg amoxicillin, 5.7 mg/kg clavulanate, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +/- SYN-007 compared to amoxicillin alone or amoxicillin/clavulanate alone as controls for both first and last doses, indicating SYN-007 did not interfere with systemic absorption of the antibiotic. Whole genome shotgun metagenomics analyses of the fecal microbiomes demonstrated both amoxicillin and amoxicillin/clavulanate significantly reduced diversity and increased the frequency of antibiotic resistance genes. Microbiome damage appeared more severe with amoxicillin/clavulanate. In contrast, with SYN-007, microbiome diversity was not significantly altered, and frequency of antibiotic resistance genes did not increase. Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically.

Dataset Information

Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium.

Publications

Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium.

Similar Datasets

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