Painkillers May Be Source of New Anti-cancer Drugs
By Merritt McKinney
Thursday, December 5, 2002
NEW YORK (Reuters Health) - By tinkering with the structure of a class of popular anti-inflammatory drugs designed to be easier on the stomach than aspirin and other arthritis drugs, it may be possible to develop new anti-cancer medications, new research suggests.
The drugs, known as COX-2 inhibitors, "can be used as a molecular starting point to generate a new class of antitumor agents," Dr. Ching-Shih Chen of Ohio State University in Columbus, the study's lead author, told Reuters Health. Chen said that he and his colleagues have started trying to develop such drugs.
COX-2 inhibitors, like older drugs such as ibuprofen and naproxen, are nonsteroidal anti-inflammatory drugs, or NSAIDs. Older NSAIDs reduce inflammation by blocking an enzyme called COX-2, but they also block an enzyme called COX-1. This enzyme helps protect the lining of the stomach, so blocking COX-1 can cause stomach irritation. COX-2 inhibitors only block COX-2, leaving the stomach-protecting COX-1 alone.
Although COX-2 inhibitors were designed to relieve pain, there have been several reports that the medications, along with other NSAIDs, may offer some protection against cancer, especially colon cancer, since the drugs' approval in the late 1990s.
According to Chen, researchers first suspected that blocking COX-2 enzymes encouraged cancer cells to kill themselves, a process called apoptosis. But in a previous study, Chen and his colleagues demonstrated that the effect of celecoxib and other COX-2 inhibitors on apoptosis was independent of their effect on COX-2. In fact, even though the drugs celecoxib (Celebrex) and rofecoxib (Vioxx) both block COX-2, celecoxib has a much more powerful effect on cancer cells.
The new research, Chen said, "extends this concept" that COX-2 inhibitors affect cancer in some other way than by blocking COX-2. According the Ohio State scientist, the experiments were aimed at identifying the structures on celecoxib and rofecoxib that trigger cell death in prostate cancer cells.
In the research, which was not funded by drug companies and is reported in the December 4th issue of the Journal of the National Cancer Institute, Chen's team first scrutinized the make-up of celecoxib and rofecoxib. Then the researchers, using COX-2 inhibitors as the base, developed a new class of compounds that target prostate cancer.
The research confirmed that COX-2 inhibitors affect cancer cells independently of their effect on COX-2.
"Our data indicate that celecoxib also inhibits other cellular targets that are crucial to the survival of cancer cells," Chen told Reuters Health. "Disruption of the functions of these cellular targets," he said," leads to cancer cell death."
Likewise, the investigators found that the compounds derived from these drugs also did not influence cancer cells by blocking COX-2. Instead, these derivatives targeted signaling pathways within prostate cancer cells.
The research "is a tour-de-force in chemical synthesis," according to Dr. Raymond N. DuBois at Vanderbilt University Medical Center in Nashville, Tennessee. He cautions in an accompanying editorial, however, that these compounds need to be studied much more extensively.
The development of new drugs "is extremely important for the success of the entire field of cancer prevention," according to DuBois, but he notes that "these new agents must be studied and tested in a systematic way to ensure their safety and efficacy."
SOURCE: Journal of the National Cancer Institute 2002;94:1732-1733, 1745-1757.