Mouse research indicates that the combination of celecoxib, a nonsteroidal anti-inflammatory drug, and 5-fluorouricil cream is up to 35 percent more effective against nonmelanoma skin cancers than treatment with cream alone, according to a presentation at the annual meeting of the Society for Investigative Dermatology.

The most common chemotherapeutic treatment for basal cell and squamous cell carcinomas is 5-fluorouracil (5-FU). However, the drug has serious side effects, said Tatiana Oberyszyn, pathologist and coauthor. "5FU is pretty harsh on the skin," she said. "It causes a lot of scaling, inflammation and pain. Patients often find the treatment worse than the cancerous lesion itself, so many stop using the drug before they should.

"And although 5FU is good at shrinking tumors, it isn't good at preventing tumors from recurring. We don't know if that's because patients don't comply with treatment or if the drug truly isn't effective in killing all of the cancer cells."

In previous work on mice, the research group had found that topically applied celecoxib prevented or delayed the onset of skin tumors induced by ultraviolet light, and did so more effectively than other drugs in its class. In these studies, mice had been treated with celecoxib following each exposure to ultraviolet light. However, the investigators found that celecoxib was not very effective in killing established tumors, whereas 5-fluorouracil was effective.

In the current study, mice were divided into five groups after they had all been exposed to ultraviolet B rays 3 times a week for nearly 4 months. The observed effects were similar to those of mild sunburn. One group of mice was treated with 5-fluorouracil cream only. A second group was treated with celecoxib cream only, and a third group, serving as a control, was treated with placebo cream. The fourth and fifth groups received the combination of 5-fluorouracil and celecoxib. One group received the drugs at the same time, whereas the other group received 5-fluorouracil in the morning and celecoxib in the afternoon. All drug treatments were given for 3 weeks.

The number of tumors decreased by up to 35 percent in both of the groups receiving the drug combination compared with the other 3 groups. Tumor size also decreased with combination therapy. "Celecoxib seemed to increase the efficiency by which 5-fluorouracil attacked cancer cells," Dr. Traci Wilgus, the presenter, said. The investigators obtained the strongest results when they applied the drugs simultaneously.
However, the addition of celecoxib unexpectedly caused intense inflammation and irritation of the mouse skin, which is why the researchers decided to treat a group with one drug in the morning and the other several hours later. This surprised the researchers, who had originally thought that the anti-inflammatory properties of celecoxib might decrease the adverse skin reactions seen with 5-fluorouracil.

"But celocoxib's ability to act in combination with 5-fluorouracil as a chemotherapeutic drug may be more powerful than its ability to inhibit inflammation," Wilgus said. "This could be why we saw increased inflammation and redness in mice treated with both drugs at the same time. We didn't see that in the animals treated with 5-fluorouracil in the morning and celecoxib later in the day.

"But giving the drugs at different times wasn't quite as effective in decreasing the number or size of tumors," she continued, adding that celecoxib has no known side effects when given alone as a topical cream. "It still had a positive effect, but the results weren't as strong."

The number of tumors decreased nearly 8-fold in mice treated simultaneously, compared with just 2-fold in mice treated with separate applications. Tumor size decreased with both regimens, although slightly more with the simultaneous application.

At 3 weeks after the final treatment, the number of new tumors, along with tumor size, rose slightly in mice treated only with 5-fluorouracil.

The researchers plan to continue pursuing this line of research in hopes of finding a way to reduce the side effects but still keep the benefits of using the drugs at the same time.