Celecoxib reduces skin damage after radiation

Inflammatory cytokine and chemokine production is mediated, at least in part, by prostaglandin E (PGE2). Cyclooxygenases, COX-I and COX-2, are two key enzymes in the conversion of arachidonic acid to PGE2. Radiation induces the overproduction of cytokines and chemokines, and it also increases PGE2 production, both locally and systemically. In this study, we tested the effects of a COX-2 inhibitor (celecoxib) after 50 Gy radiation of MCa-35 tumor and cutaneous tissues of C3H/He mice. Preclinical toxicity endpoints and associated alterations in chemokine production and cellular infiltrates were measured. Celecoxib was given by daily gavage (50 mg/kg for 15 days), with the first dose delivered either 2 hours before, 2 days after, or 7 days after a single dose of radiation. Celecoxib-treated animals had less inflammation of the dermis compared with saline-treated controls. Severe skin dermatitis occurred in 23.8% (5/21) of mice treated with 50 Gy, whereas only 17.6%, 5.3%, and 11.1% of mice in the 2-hour pre-, or the 2-day post-, and 7-day postirradiation groups, respectively, had severe dermatitis on day 20. The decreased skin toxicity scores were associated with a reduction of both blood vessels and focal necrosis in MCa-35 tumors. Celecoxib also significantly decreased C-C family chemokine (Rantes and MCP-1) mRNA expression in irradiated skin tissues, but not in tumor tissues, which was accompanied by a decrease in skin mRNA expression of both C-C (CCR2 and CCR5) and C-X-C (CXCR2 and CXCR4) chemokine receptors. A significant positive correlation was also found between skin damage (skin scores) and chemokine and its receptor mRNA expression in radiation-treated mice. Finally, celecoxib also decreased the infiltration of monocytes and neutrophils in locally irradiated tumor and surrounding normal tissue. The differential effects of celecoxib on inflammation help to explain the selective protection by celecoxib of irradiated cutaneous tissues without a concurrent protection of MCa-35 tumors.