Targeting angiogenic processes by combination rofecoxib and ionizing radiation

Tumor growth and angiogenesis are interdependent. Cyclooxygenase (COX) cata lyzes the synthesis of prostaglandins from arachidonic acid. Nonsteroidal a ntiinflammatory drugs (NSAIDs) inhibit COX-mediated synthesis of prostaglan dins. COX-1 is constitutively expressed in a wide range of tissues, whereas COX-2 is cytokine inducible. Enhanced COX-2 expression has been attributed a key role in the development of inflammation and related processes observ ed in pathologically altered disease states. Two specific COX-2 inhibitors, namely rofecoxib (Vioxx) and celecoxib (Celebrex), both oral agents and U. S. Food and Drug Administration approved, have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pai n and inflammation in osteoarthritis, with decreased risk of gastrointestin al damage. Little is known about how angiogenesis is affected by the combin ation of rofecoxib and radiation. We have evaluated the combination of rofe coxib, at various concentrations, and radiation on cytokine-induced angioge nesis in vitro. We have found that rofecoxib inhibited endothelial cell pro liferation, migration, and tube formation (differentiation) at clinically r elevant doses, In combination With radiation, inhibition of endothelial cel l function further increased twofold. The combination of rofecoxib and radi ation suggests a complementary strategy with clinical ramifications to targ et angiogenesis-dependent malignancies.