by J. Strax
PSA Rising, March 1, 2005 -- Celebrex and Vioxx, two drugs of a class called COX-2 inhibitors, were designed (and massively marketed) as painkillers that would be easy on the stomach. They turn out to be no more effective as painkillers than many over the counter drugs. Far more seriously, they increase risk of heart attack and cardiovascular damage. Celebrex, though, looks promising as an anti-cancer drug. Research at the University of North Carolina, at the Mayo and now at Weill Medical College of Cornell University suggests that clinically and in the laboratory, Celebrex fights tumors.
Vioxx was pulled off the market last fall by its maker Merck & Co. and faces legal suits. Last month a panel agreed unanimously that COX-2 inhibitors pose heart risks. The panel voted 31-1 to advise the Food and Drug Administration (FDA) to allow Celebrex to stay on the market, 17-13 with two abstaining for Bextra (another in the same clss of drugs) and 17-15 for Vioxx. The panels called for the strongest of warnings (a "black-box") on all all the drugs' labels and restrictions on advertising.
Meanwhile the promising anti-cancer properties of COX-2 inhibitors, especially of Celebrex, are not forgotten. Celebrex was actually in tests to see if it can prevent precancerous colon polyps when data showed that at twice or more the normal dose it more than doubled heart deaths, heart attacks, and strokes . Pfizer, Celebrex's maker, closed down this colon polyp trial. But already, a month earlier, researchers at Mayo had reported that in mice, Celebrex reduced breast cancer tumors.
This effect was associated with increased programmed cell death, or apoptosis, in the breast tissue of the mice. Celecoxib-induced cell death, the rearchers said, was associated with two molecular events involving pathways that lead to apoptosis. The COX-2 inhibitor increased expression of the Bax protein, which is known to help trigger apoptosis. Further, the introduction of celecoxib resulted in reduced activity of an anti-apoptotic protein, Akt, known to promote cell survival.
Now, going further and switching to prostate cancer cells, scientists at the Weill Medical College of Cornell University in New York have found that Celebrex reduces levels of a key protein, cyclin D1, that's critical for cell replication. Their work is published in the March 1 issue of the journal Clinical Cancer Research.
As it happens, they designed their studies to find out if Celebrex attacks prostate cancer cells in a way that differs from Vioxx (rofecoxib).
"It is well established that COX-2 is a significant and rational target for anti-cancer therapy," said Andrew Dannenberg, M.D., director of cancer prevention at the Weill Medical College of Cornell University and senior author of the paper.
"These studies suggest that celecoxib exerts a second mode of action independent of its known anti-inflammatory mechanism that imposes further restrictions on the proliferation of prostate cancer cells. The results provide potentially important insights into our understanding of the overall anti-tumor activity of selective COX-2 inhibitors."
Dannenberg and a team of investigators discovered this new mechanism by applying celecoxib to prostate cancer cells that failed to express COX-2. Here, the scientists observed that the celecoxib-treated cancer cells did not replicate as rapidly as untreated cells. After further analysis, they found the drug worked by suppressing amounts of cyclin D1, a protein that's essential if cells are to grow, divide and spread.
The scientists also attempted to replicate the experiment with Vioxx substituting for celecoxib. In this case, the prostate cancer cells continued to flourish.
"These results support the notion of a unique action by celecoxib that is independent of COX-2, and that's different from Vioxx," said Dannenberg.
"These beneficial effects were observed at concentrations of celecoxib that occur in humans," added Dannenberg. "This increases the likelihood that our findings are clinically relevant."
Dannenberg and his colleagues then demonstrated that celecoxib worked in animals that served as hosts for human prostate tumors. In this animal model, celecoxib not only was shown to reduce proliferation of cancer cells, but also reduced the growth of blood vessels at the tumor sites. As a result, tumor mass and blood vessel density in the treated animals was about half that observed in the untreated animals.
Contributing to the studies, along with Dannenberg, were Kotha Subbaramaiah, Baoheng Du and Mindy Chang from Weill Medical College of Cornell University, New York, N.Y.; Manish Patel, Carlos Cardon-Cardo, and Howard Thaler, Memorial Sloan-Kettering Cancer Center, New York, N.Y.; and Peiying Yang and Robert Newman, UT M.D. Anderson Cancer Center, Houston, Texas.
posted March 1, 2005
