An interdisciplinary team of researchers, led by Axel H. Schšnthal, at the Keck School of Medicine of USC ( University of Southern California ) has been studying the effects of an analog of Celecoxib that does not have ability to block the activity of cyclooxygenase-2 ( COX-2 ), an enzyme integral to the inflammatory process.

The researchers showed that the analog manages to halt tumor growth even in drug-resistant lines of multiple myeloma cells.

The work is published in the journal Blood.

Most of the attention Celecoxib ( Celebrex ) has received in recent years has been as a result of its anti-inflammatory effects and, most recently, the withdrawal of the two other main COX-2 inhibitors on the market-Vioxx and Bextra- after data unearthed linking them to an increased risk of heart attack in some patients.
Celebrex remains on the market, but now carries a "black box" warning about the potential for cardiovascular side effects.

Celecoxib is more than just an anti-inflammatory agent.

Over the past couple of years, researchers have begun to recognize that cyclooxygenase-2 can sometimes play a role in cancer; for instance, they've shown that the enzyme is overexpressed by multiple myeloma cells, and that this is a predictor of a poor outcome for the patient. Thus, it seemed clear that a cylooxygenase inhibitor might be able to turn things around.

In several laboratory studies, the COX-2 inhibitor Celecoxib showed an ability to target several of the growth pathways; further studies showed that Celecoxib's anticancer activity appeared to be independent from its COX-2 inhibition.
The analog - 2,5-dimethyl-Celecoxib or DMC - retains the ability to stop cancer growth despite the fact that it doesn't inhibit the activity of COX-2.

"Amazingly," the researchers noted in the Blood paper, "these growth-inhibitory effects take place even in cells that otherwise are highly resistant to the inhibitory effects of various anti-cancer drugs that are commonly used in the clinic for the treatment of cancer patients."

The fact that DMC is as potent-or, says Schšnthal, even more potent, even at lower doses-than Celecoxib despite having no ability to inhibit COX-2 is important, the researchers say, especially in light of the recently revealed side effects of COX-2 inhibitory drugs. " Bearing in mind that substantially increased daily dosages of these drugs are considered-and probably necessary-for cancer prevention or cancer therapy, the increased risk of cardiovascular failure is of considerable concern," they wrote in the Blood paper. But because the unwanted cardiovascular side effects of Celecoxib are connected to its ability to inhibit COX-2, Schšnthal speculates that DMC, which lacks that ability, might not cause similar problems.

Schšnthal notes that his research points to Celecoxib in particular as being unique in its ability to slow or stop tumor growth. All the COX-2 inhibitors are able to block the activity of cyclooxygenase-2, he says, but only Celecoxib and its analogs seem able to arrest growth and induce cellular suicide ( apoptosis ), even in cells that don't produce COX-2.

Source: University of Southern California, 2005


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