Oral celecoxib inhibited basal cell carcinoma carcinogenesis in mice and had a chemopreventive effect on basal cell carcinoma in humans with less severe disease, results from a novel investigation demonstrated.
The findings, published in Cancer Prevention Research, help to explain what causes basal cell carcinoma tumors, lead study author Jean Y. Tang said in an interview.
"We always used to think that BCC was caused only by mutations in the hedgehog pathway," said Dr. Tang of Stanford (Calif.) University. "Now we know that the [cyclooxygenase] enzyme is also important for BCC development. That means we can find drugs that target COX. That should prevent or treat BCCs."
She and her associates conducted two trials: one in mice and one in humans.
For the mouse trial, the investigators compared the relative anti-BCC effects of genetic deletion and nonsteroidal anti-inflammatory pharmacologic inhibition of cyclooxygenase enzymes in the skin of Ptch+/- mice (Cancer Prev. Res. 2010; 3[1]:25-34).
For the phase II human trial, which began in May of 2001 at four clinical sites, 60 patients with basal cell nevus syndrome were randomized to placebo or to 200 mg celecoxib twice daily for 24 months. Patients with this syndrome are genetically predisposed to developing multiple basal cell carcinomas.
Participants returned to the study sites every 3 months for physical examinations, which included the measurement and counting of BCCs.
Patients discontinued taking study medications in December 2004 after news of potential cardiovascular adverse events in persons treated with celecoxib (N. Engl. J. Med. 2005;352:1071-80).
In the mouse trial, genetic deletion of COX1 or COX2 decreased microscopic tumor burden by 75% while pharmacologic inhibition with celecoxib reduced microscopic BCCs by 35%. "That tells us that the [COX] enzyme is important for BCC tumor development," Dr. Tang said.
In the human trial, patients in the placebo group had a 37% increase of BCCs per year, compared with a 26% increase among patients in the celecoxib group, a difference that was not statistically significant. However, when the researchers stratified patients by the number of BCC tumors at baseline (fewer than 15 vs. 15 or more), celecoxib reduced the change in the number of BCCs in patients with fewer than 15 BCCs at baseline (48% vs. 22% in the placebo group) but did not have an effect in patients with 15 or more BCCs at baseline.
"That's the surprising part," Dr. Tang commented. "We were hoping that this drug would have more of an impact on the patients with really severe disease."
The researchers also found that patients in the placebo group who had fewer than 15 BCCs at baseline had a 50% increase in BCC burden per year, while patients in the celecoxib group had a 20% increase, a difference that was statistically significant.
Dr. Tang said that the findings "open the field for people to explore other drugs that inhibit the COX enzymes for BCC treatment or prevention. There are safer drugs that don't have as much cardiovascular toxicity [as celecoxib]. For example, aspirin, ibuprofen, and other COX1 and COX2 inhibitors may work."
She acknowledged certain limitations of the study, including the fact that the human trial was limited to 60 patients with basal cell nevus syndrome, which is also known as Gorlin's syndrome. "Most patients with sporadic BCCs don't have the Gorlin's syndrome," she explained. "So we don't know if celecoxib would work against sporadic BCCs in non-Gorlin's patients."
In an accompanying editorial, Dr. Charles M. Rudin of the department of oncology at Johns Hopkins University, Baltimore, called the findings "encouraging" but emphasized that they should be interpreted with caution (Cancer Prev. Res. 2010; 3[1]:1-3).
"In each of their several murine experiments, the effect of genetic or pharmacologic COX inhibition on tumor burden was predominantly attributable to a decrease in tumor size, with a lesser, if any, effect in reducing tumor number," he noted. "This result suggests that the primary effect of COX inhibition may be on proliferation rate rather than on malignant transformation per se. In this scenario, the reported minor decreases in tumor number could reflect maintenance of a small number of tumors at a size below clinical detection. These observations may be reminiscent of the differentiating effects of retinoids, which may suppress tumorigenesis, but in a transient and thus questionable manner."
The researchers had no conflicts of interest to disclose.
The study was funded by grants from the National Institutes of Health, the Mike Rainen Family Foundation, and the National Center for Research Resources (University of California, San Francisco).