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| Kofi |
 Posted: Thu May 12, 2005 3:58 am |
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http://www.sciencedaily.com/releases/2005/05/050501133736.htm
Source:
Vanderbilt University Medical Center
Date:
2005-05-02
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Blocking COX-1 Slows Tumor Growth In Mice
Blocking the COX-1 enzyme -- not COX-2 -- might lead to a way to prevent
and treat the most common and fatal form of ovarian cancer, researchers
at Vanderbilt University Medical Center reported this week.
The finding, that COX-1 inhibition slowed the growth of epithelial
ovarian tumors in a mouse model of the disease, is surprising, said
Sudhansu K. Dey, Ph.D., senior author of the paper and director of the
Division of Reproductive and Developmental Biology in the Vanderbilt
Department of Pediatrics.
Previous studies have linked high levels of another cyclooxygenase
enzyme, COX-2, to colorectal and other cancers. "But this is the
exception," said Dey, also professor of Cell & Developmental Biology and
Pharmacology.
"These results establish the foundation for further studies and clinical
trials using the novel approach of targeting COX-1 for the prevention
and treatment of ovarian cancer," the researchers concluded.
Dey said further studies should be conducted to determine whether
aspirin and other non-steroidal anti-inflammatory drugs, which block
both COX enzymes, might improve treatment of epithelial ovarian cancer.
The study, posted Sunday on the Web site of the journal Cancer Research,
was led by Takiko Daikoku, Ph.D., research assistant professor of
Pediatrics at Vanderbilt.
According to the American Cancer Society, more than 22,000 women in the
United States will be diagnosed with ovarian cancer this year, and more
than 16,000 will die from the disease. Ovarian cancer is the fourth
leading cause of cancer death in American women after lung, breast and
colorectal cancer.
Eighty-five percent of human ovarian tumors arise from the epithelium or
surface layer of tissue that surrounds the ovaries. While the incidence
of ovarian cancer has declined recently, the death rate has not, in part
because it is difficult to diagnose the disease in the early stages.
Several previous studies have reported high COX-2 levels in ovarian
tumors. Most of these, however, used antibodies to detect COX-2
expression. "We now know that many of the commercially available
antibodies cross react with both COX-1 and COX-2," Dey said.
The Vanderbilt researchers used multiple techniques, and in 2003
reported that COX-1 was over-expressed and promoted the growth of blood
vessels in human epithelial ovarian tumors.
A year earlier, Sandra Orsulic, Ph.D., and her colleagues at the
Memorial Sloan-Kettering Cancer Center in New York reported that they
were able to induce ovarian cancer in a mouse model by using a virus to
deliver two cancer-causing genes into ovarian surface epithelial cells
that lacked a tumor suppressor gene.
In the current study, the Vanderbilt researchers used Orsulic's model to
test whether celecoxib (Celebrex), a selective COX-2 inhibitor, and
SC-560, an experimental drug that selectively blocks COX-1, slowed tumor
growth when these cells were transplanted into mice.
They found that while Celebrex had little effect, the COX-1 blocker
dramatically reduced tumor growth. The drug also blocked production by
COX-1 of prostacyclin, a member of a family of potent, hormone-like
substances called prostaglandins that play a role in a wide variety of
physiological functions including pain, inflammation and, presumably,
cancer.
Whereas prostacyclin is the predominant prostaglandin found in mouse
ovarian tumors, another prostaglandin, PGE2, seems to be generated in
higher quantities in human ovarian cancers. This suggests that it's not
the particular enzyme -- COX-1 or COX-2 -- but downstream factors,
including prostaglandins, that initiate tumor growth, Dey said.
Last fall, for example, the Vanderbilt researchers reported that
silencing a cellular receptor called PPAR-- interfered with the ability
of PGE2 to promote pre-cancerous colon polyps in mice.
Other researchers who contributed to the ovarian cancer study were
Dingzhi Wang, Ph.D., research associate professor of Medicine; Susanne
Tranguch, graduate student in Cell Biology; Jason D. Morrow, M.D.,
director of Clinical Pharmacology; Orsulic, now at Massachusetts General
Hospital; and Raymond N. DuBois, M.D., Ph.D., director of the
Vanderbilt-Ingram Cancer Center.
###
The study was supported by the National Cancer Institute, the Mary Kay
Ash Charitable Foundation and the American Association of Cancer
Research.
------------------------------------------------------------------------
This story has been adapted from a news release issued by Vanderbilt
University Medical Center.
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