Blocking the COX-1 enzyme might be the answer in ovarian cancer treatment

May 2 2005

Researchers at Vanderbilt University Medical Center in a new report say that 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.

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 says they are surprised by the results which show that COX-1 inhibition slowed the growth of ovarian tumours in mice with the disease, as previous studies have linked high levels of another cyclooxygenase enzyme, COX-2, to colorectal and other cancers.

Dey says the results will establish the foundation for further studies and clinical trials using this new approach of targeting COX-1 for the prevention and treatment of ovarian cancer and suggests 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 ovarian cancer.

The American Cancer Society says that 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 which is the fourth leading cause of cancer death in American women after lung, breast and colorectal cancer.

Almost all ovarian tumours arise from the epithelium or surface layer of tissue that surrounds the ovaries and though the incidence of ovarian cancer has declined recently, the death rate has not because of the difficulty in diagnosing the disease in its early stages.

Dey says that previous studies have reported high COX-2 levels in ovarian tumours but most of these used antibodies to detect COX-2 and it is now known that many of the commercially available antibodies cross react with both COX-1 and COX-2.

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 tumours.

In 2002 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 tumour suppressor gene.

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 tumour growth when these cells were transplanted into mice and they found that while Celebrex had little effect, the COX-1 blocker dramatically reduced tumour 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, possibly cancer.

Whereas prostacyclin is the predominant prostaglandin found in mouse ovarian tumours, another prostaglandin, PGE2, seems to be generated in higher quantities in human ovarian cancers and suggests that it is not the particular enzyme - COX-1 or COX-2 - but downstream factors, including prostaglandins, that initiate tumour growth, says Dey.

The Vanderbilt researchers reported last year that silencing a cellular receptor called PPARa interfered with the ability of PGE2 to promote pre-cancerous colon polyps in mice.

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. 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.

http://www.mc.vanderbilt.edu/