Cyclooxygenase-2 (COX-2) enzyme inhibitors and radiotherapy: preclinical basis

Cyclooxygenase-2 (COX-2), an enzyme induced by proinflammatory cytokines, mitogenic substances, oncogenes, growth factors, and hypoxia, among others, is involved in the metabolic conversion of arachidonic acid to prostaglandins in inflamed tissues and neoplasia. COX-2 is often overexpressed in malignant tumors and premalignant lesions and is linked to carcinogenesis, maintenance of progressive tumor growth, and facilitation of metastatic spread. Because COX-2 may also be a determinant of tumor radioresistance, its inhibition or inhibition of its products (prostaglandins) may improve tumor response to radiotherapy. Preclinical studies have shown that treatment with selective COX-2 inhibitors significantly enhances tumor response to radiation without appreciably affecting normal tissue radioresponse. The underlying mechanisms of the COX-2 inhibitor-radiation interactions seem to be multiple, with the enzyme inhibitor directly or indirectly augmenting tumor cell destruction by radiation. Thus, use of selective COX-2 inhibitors is a potential approach for improving cancer radiotherapy.