COX-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer

Lung cancer is the leading cause of cancer death in the USA. Conventional therapy using chemotherapy, radiation therapy, and a combination of the two, has yielded modest improvement in patient outcome. Dysfunction and dysregulation of many molecular processes and signaling pathways are involved in the development and growth of malignant lung tumors, and in conferring resistance to standard cancer treatments. Cyclooxygenase (COX)-2, an enzyme involved in prostaglandin production in pathologic states, is often overexpressed in premalignant and malignant lesions. Overexpression of COX-2 in lung cancer is associated with more aggressive biologic tumor behavior and adverse patient outcome. In preclinical studies, inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These findings quickly led to clinical studies. Phase I and II clinical trials of the combination of selective COX-2 inhibitors with radiotherapy, chemotherapy, or both in patients with lung cancer have been initiated and some preliminary results are available. In this review, the relationship between overexpression of COX-2 and lung cancer, the antitumor effect of selective COX-2 inhibitors, and the rationale for using selective COX-2 inhibitors combined with radiotherapy and chemotherapy, will be described. Current clinical protocols and preliminary findings will also be summarized.