May 5, 2003 COLUMBUS, Ohio -- Researchers from Ohio State University found that a common pain relief medication seems to increase the effectiveness of a drug used to treat skin cancer.
Experiments in mice showed that the combination of celecoxib -- a prescription-only non-steroidal anti-inflammatory drug (NSAID) -- and a cream commonly used to treat nonmelanoma skin cancer was up to 35 percent more effective in reducing the number of skin cancer tumors than treating such lesions with the cream alone.
"Even though there is an alarming number of new skin cancer cases every year, the standard chemotherapy drugs we have to use aren't completely effective in treating this disease," said Traci Wilgus, a study co-author and a postdoctoral fellow in the department of pathology in Ohio State's College of Medicine and Public Health.
She and her colleagues presented their findings May 4 at the annual meeting of the Society for Investigative Dermatology meeting in Miami Beach.
Each year, more than one million Americans develop either basal cell or squamous cell carcinoma -- the two forms of nonmelanoma skin cancer. Both types affect cells in the skin's epidermal layer while melanoma, the most serious form of skin cancer, affects cells that make up the skin's pigment.
A compound called 5-fluorouracil, or 5FU, is the drug most often used to treat nonmelanoma skin cancer. (5FU is known by the brand name Efudex.) But the drug has serious side effects, said Tatiana Oberyszyn, a study co-author and an assistant professor of pathology at Ohio State.
"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, Oberyszyn and her colleagues found that topically applied celecoxib (known by the brand name Celebrex) prevented or delayed the onset of skin tumors induced by ultraviolet light -- and it did so better than other NSAIDs. In these studies, mice had been treated with celecoxib following each exposure to ultraviolet light.
But they also found that celecoxib wasn't very effective in killing established tumors. 5FU, on the other hand, essentially destroys cancer cells that are present.
Mice in the current study were put into five groups. The animals had already been exposed to ultraviolet B (UVB) rays three times a week for nearly four months. The effects were similar to mild sunburn. The drug treatments lasted for three weeks.
One group of mice was treated with 5FU only; another group was treated with celecoxib only; and a third group, serving as a control, was treated with a placebo. All of the drugs were applied to the skin in cream form.
The researchers treated mice in the fourth and fifth groups with both 5FU and celecoxib; however, one group received both drugs at the same time, while the other group was given 5FU in the morning and celecoxib in the afternoon. All of the drug treatments lasted for three weeks.
The number of tumors decreased by up to 35 percent in both of these latter groups, compared to the other three groups. Tumor size also decreased.
"Celecoxib seemed to increase the efficiency by which 5FU attacked cancer cells," Wilgus said. She and her colleagues saw the strongest results when they applied 5FU and celecoxib at the same time. However, for unknown reasons, the addition of celecoxib caused intense inflammation and irritation of the mouse skin -- that's why the researchers decided to treat one group with 5FU in the morning and with celecoxib several hours later.
The researchers originally thought that the anti-inflammatory properties of celecoxib might decrease 5FU's side effects.
"But celocoxib's ability to act in combination with 5FU as a chemotherapeutic drug may be more powerful that 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 5FU 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 eight-fold in the mice treated with the combined drugs, and just two-fold in the mice treated with separate applications. Tumor size decreased with both regimens, although slightly more with the simultaneous application.
Three weeks after the final treatment, the number of new tumors, along with tumor size, rose slightly in mice treated only with 5FU.
The researchers said they plan to continue pursuing this work in hopes of finding a way to reduce the side effects but still keep the benefits of using the drugs at the same time.
"We hope to eventually reduce the dose of 5FU enough that we get less side effects along with increased efficacy," Wilgus said.
Support for this research came from the National Institutes of Health and the Ladies Auxiliary VFW Cancer Research Fellowship. ICN Pharmaceuticals, Inc., supplied the Efudex for this study. The company's headquarters are located in Costa Mesa, Calif.
Wilgus and Oberyszyn conducted the study with Thomas Breza, a medical student at Ohio State University, and Jennifer Hatton, a graduate student in the Integrated Biomedical Graduate Program at Ohio State.
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