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Combining NSAIDs With Chemotherapy May Improve Cancer Therapy

Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and celecoxib (sold as Celebrex), were being hailed as promising cancer prevention drugs . However, the latest studies have concluded that in most cases the adverse side effect of these drugs -- including risk of cardiovascular and kidney disease -- outweigh the potential benefit.

However, certain NSAIDs may be better suited to treating cancer, in combination with standard therapies, rather than preventing it, according to new research by scientists at the University of Iowa Roy J. and Lucille A. Carver College of Medicine.

"The real debate comes down to use of these compounds in two settings: cancer prevention, which involves long-term use of a drug, and cancer treatment involving short-term, focused use of the drug," said Douglas Trask, M.D., Ph.D., UI associate professor of otolaryngology head and neck surgery. "Published studies show that heart and kidney problems occur with long-term use, especially when used for more than one year. While there appear to be cardiorenal effects of NSAIDs even with short-term use, these risks may be minor compared to the potential benefit to treat cancer more effectively."

Two new UI studies show that the NSAID celecoxib has potent anticancer activity, which is associated with the drug's ability to disrupt the cell cycle -- the orderly, multi-step process by which cells divide.

In particular, the experiments showed that celecoxib specifically kills head and neck cancer cells in the S phase of the cell cycle, where the cell synthesizes new DNA and replicates its genetic material.

"The finding that the cell killing effect takes place in S phase is particularly exciting because one of the standard therapies for most cancers -- chemotherapy -- often has its maximal effect at that stage of the cell cycle," Trask said. "We're hopeful that our results will lead to a clinical trial where we combine celecoxib with chemotherapies for head and neck cancer."

Trask's research team included Jonathan Bock, M.D., a UI resident in otolaryngology and lead author of the two studies published in recent issues of the journals Molecular Carcinogenesis and Cancer Research. Prabhat Goswami, Ph.D., UI assistant professor, and Frederick Domann, Ph.D., UI professor, both faculty in radiation oncology and in the Free Radical and Radiation Biology Graduate Program, also were part of the UI team. Trask, Goswami and Domann all are members of the Holden Comprehensive Cancer Center at the UI.

Goswami and Domann added that when radiation is used to treat head and neck cancers after surgery, the cells most resistant to radiation therapy are in the S phase. Thus celecoxib's selective killing of cells in S phase suggests this class of drug may target the radio-resistant cells, and use of the drug together with radiation might provide better tumor control than radiation alone.

Because inflammation is thought to play a role in the development of certain cancers, numerous studies have investigated the role of nonsteroidal anti-inflammatory drugs in cancer prevention. However, few studies have systematically evaluated the relative anticancer activity of different NSAIDS.

In one study, published in the April 5 online issue of Molecular Carcinogenesis, the UI scientists tested 10 commercially available NSAIDs against head and neck cancer cells. They found that celecoxib and sulindac sulfide, (sold as Clinoril sulfide) are particularly effective at slowing cancer cell proliferation and at killing cancer cells. Of these two, celecoxib is by far the most potent, killing up to 60 percent of head and neck cancer cells under the study conditions. None of the other 10 NSAIDs in the study, including aspirin, naproxen (Aleve) or rofecoxib (Vioxx), showed effective anticancer activity.

The experiments also indicated that celeco xib and sulindac sulfide's anticancer activity was mediated through cell cycle inhibition and induction of apoptosis (cell suicide) and was not related to the drugs' anti-inflammatory properties.

In a second study, published in the April 15 issue of Cancer Research, the UI team shows how celecoxib exerts its anticancer effect by altering protein expression in ways that disrupt the cell cycle and lead to cell death.

Cells go through three phases before they divide: G1 phase, where the cell grows and makes protein; S phase, where the cell makes DNA and replicates its chromosomes; and G2 phase, where the cell prepares for division. The cell cycle also contains several well-defined checkpoints where the growing cell stops and "decides" that things are ready to move on to the next stage.

The UI research found that celecoxib alters the expression of G1 checkpoint proteins and significantly decreases the activity of a protein called E2F1. This activity is required for cells to move through the cell cycle and also is crucial for S phase activities like DNA repair. Celecoxib's inhibition of E2F1 activity may be a reason for the drug's observed S phase-specific toxicity.

Trask notes that the study results have identified a set of biomarkers that appear to predict how effective a drug is at killing cancer cells, which should facilitate screening of other compounds that might have anticancer effects similar to celecoxib, but could be used in lower, perhaps safer, doses.


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