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Custom Rodents, COX-2 Show Value Against Skin Cancers

By Ray Fleming

Basal cell carcinoma (BCC), the most common of all human cancers, affects 750,000 Americans a year. In fact, estimates are that one in three Caucasians born in the U.S. after 1994 will develop such a skin cancer in their lifetime. Despite these sobering statistics, however, the battle against this and other tumor-producing skin cancers like squamous cell carcinoma (SCC) has just taken a turn for the better. With support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, scientists have notched two recent victories: the first mouse model of human BCC and a reduction in mouse SCC tumors by the COX-2 inhibitor celecoxib.

At least one mouse model of skin cancer — that of SCC — has been created experimentally by exposure to ultraviolet light. This model has yielded much information about the genetic and cellular components of the disease. But until recently, scientists had been unable to produce BCC-like tumors in mice either through chemicals, UV light exposure or ionizing radiation. Now, the University of California, San Francisco's Dr. Michelle Aszterbaum and her colleagues have found that ptch+/- mice, which have an alteration in the tumor suppressor gene, develop a high incidence of BCC-like tumors in response to chronic UV exposure or a single dose of ionizing radiation. This discovery confirms the importance of protecting against UV and radiation in preventing human skin cancer. And because this new mouse model can reproduce tumors that have similarities to BCC tumors, it is ideal for testing gene therapy, chemoprevention and chemotherapy against human tumors.

At the University of Rochester Medical Center, Dr. Alice Pentland and her colleagues have used another laboratory mouse — the hairless mouse — to move toward improved treatment for SCC. In their study, mice with SCC tumors produced by previous UV light exposure were divided into two groups: a control group and one fed a diet containing celecoxib, a new COX-2 inhibitor used in the treatment of arthritis. (COX-2 inhibitors block an enzyme known to stimulate inflammation in the body.) After 10 weeks, the mice fed the celecoxib diet had about half the number of tumors present in the control group. The drug was most effective at reducing new SCC tumor formation, suggesting that celecoxib might be a useful way to prevent some human skin cancers resulting from previous UV light exposure. However, additional studies need to be done.

"These two studies will definitely help us bring skin tumors into sharper focus," said NIAMS director Dr. Stephen Katz.

Gene Found for Papillon-Lefevre Syndrome

An international team of scientists has tracked down the gene responsible for Papillon-Lefevre syndrome (PLS), a rare but devastating condition that produces areas of thick, cracked skin and causes people to lose all their teeth by the time they are young adults. The rapid loss of both baby and permanent teeth mirrors the most severe forms of periodontal (gum) disease. The investigators feel that identification of the gene for PLS may help determine the process by which periodontal disease attacks the general population.

Dr. Thomas Hart of the University of Pittsburgh directed the study that examined the DNA from five Turkish families that had both normal and PLS-affected members. By following the inheritance pattern of known DNA markers, the responsible gene was narrowed to a small region of chromosome 11. A detailed analysis of this region found mutations in the gene that codes for an enzyme called cathepsin C. The study, which was supported by NIDCR, appeared in the December issue of the Journal of Medical Genetics.

"The identification of cathepsin C mutations in PLS will help scientists to better understand both normal and abnormal development of the skin and gums," said Hart. "Understanding how defective cathepsin C causes destruction of the gums in PLS may help us understand what causes more common forms of periodontal disease."

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