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CDB-2914 may be an effective fibroid treatment.

Between 20 and 40 percent of women older than 35 have uterine fibroids. Also known as leiomyomas, uterine fibroids are benign (non-cancerous) tumors in the muscular wall of the uterus. They can range from the size of a grape to the size of a cantaloupe. Although otherwise benign, fibroids may cause heavy menstrual flow and pain in some women. The discomfort and bleeding associated with fibroids lead many women with the condition to have hysterectomies, or surgical removal of the uterus. As many as one-quarter to one-half of the 600,000 hysterectomies performed annually in the United States are performed to treat fibroids.

Studies of the drug CDB-2914 suggest that it may be an effective treatment for fibroids. It is possible that CDB-2914 could be delivered into the body via a vaginal ring or intrauterine system. These studies were conducted by obstetrician/gynecologist Takeshi Maruo and his team at Japan's Robe University, in collaboration with two Council biomedical scientists: reproductive endocrinologist Regine L. Sitruk-Ware and obstetrician/ gynecologist Elof D.B. Johansson. Sitruk-Ware is executive director of product research and development at the Council's Center for Biomedical Research, and Johansson is a Population Council vice president, responsible for the center. Maruo is a member of the Council's International Committee for Contraception Research (ICCR). The Population Council and its ICCR are also studying CDB-2914 for use as a potential contraceptive.

Progesterone receptor modulator

Several lines of research suggest that the female hormone progesterone plays a role in the growth of fibroids. Progesterone exerts its influence by binding with molecules, known as progesterone receptors, in cells. When progesterone binds with the progesterone receptor, it activates the receptor. The activated receptor determines when specific genes will turn on. When a gene turns on, it produces the proteins that tell the cell what to do.

CDB-2914 is a member of a class of drugs known as progesterone receptor modulators, which also bind to the progesterone receptor, preventing progesterone from binding with it. When progesterone cannot bind, to the receptor, the genes with which it interacts remain inactive.

Maruo and his team performed in vitro culture studies mixing CDB-2914 with cells from uterine fibroids and with cells from normal uterine smooth muscle. The scientists measured the levels of various proteins and looked for growth (or lack of growth) in those cultured cells. The tissues were taken from women with normal menstrual cycles who underwent fibroid removal or hysterectomy. All the women were being treated for fibroids at Robe University Hospital.

Apoptosis and angiogenesis

The researchers looked at levels of proteins associated with two processes--apoptosis and angiogenesis--that influence the growth of tumors. Apoptosis is genetically programmed cell death. Unlike cell death caused by disease, however; apoptosis is normal, orderly, and generally not harmful. Angiogenesis is the growth of new blood vessels. This process is essential to wound healing, but also to the growth of fibroids and other tumors.

The researchers found fewer fibroid cells in cultures treated with CDB-2914 than in untreated cultures. They also found that fibroid-cell cultures treated with CDB-2914 had lower concentrations of two proteins: proliferating cell nuclear antigen (PCNA) and Bcl-2. If present at higher levels, PCNA and Bcl-2 would induce fibroid growth by stimulating cell proliferation and by inhibiting apoptosis, respectively. The researchers found that in fibroid ceils, but not in cells from normal uterine smooth muscle, CDB-2914 reduces levels of proteins that stimulate angiogenesis: adrenomedullin and vascular endothelial growth factor. Conversely, CDB-2914 increases the amount of two proteins that trigger apoptosis: cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase.

"These results," says Maruo, "suggest that CDB-2914 may inhibit the growth of uterine fibroids, while not affecting the surrounding healthy smooth muscle. These findings contribute additional evidence that CDB-2914 may be useful in the treatment of uterine fibroids."

SOURCES

Xu, Qin, Shigeki Takekida, Noriyuki Ohara, Wei Chen, Regine Sitruk Ware, Elof D.B. Johansson, and Takeshi Maruo. 2005. "Progesterone receptor modulator CDB-2914 down regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5'-diphosphateribose) polymerase expression in cultured human uterine leiomyoma cells," Journal of Clinical Endocrinology& Metabolism 90(2): 953-961.

Xu, Qin, Noriyuki Ohara, Wei Chen, Jin Liu, Hiroko Sasaki, Akira Morikawa, Regine Sitruk-Ware, Elof D.B. Johansson, and Takeshi Maruo, 2006. "Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells," Human Reproduction 21 (9): 2408-2416.

OUTSIDE FUNDING

HRA Pharma (Paris, France), Japanese Ministry of Education, Science and Culture, and the Ogyaa-Donation Foundation of the Japan Association of Obstetricians and Gynecologists
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Title Annotation:progesterone receptor modulators
Publication:Population Briefs
Geographic Code:1USA
Date:Sep 1, 2006
Words:758
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