Improvement of radiotherapy or chemoradiotherapy by targeting COX-2 enzyme

Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radioresistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Solid evidence exists that administering standard chemotherapeutic agents during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites. These therapeutic improvements, however, have been achieved at the expense of considerable normal tissue toxicity. To improve chemoradiotherapy further, there have been extensive explorations of the potential of newer chemotherapeutic agents, including irinotecan (CPT-11, Camptosar) and other topoisomerase inhibitors. Preclinical studies have shown that these agents are potent radiosensitizers, providing a strong biologic rationale for using these drugs in combination with radiotherapy. These studies also generated information critical for designing effective treatment schedules in clinical settings. The therapeutic efficacy of topoisomerase inhibitor-radiation combinations is currently being tested clinically. Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, that promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, and hence may serve as potential targets for augmentation of radio (or chemo) response. COX-2 is often overexpressed in premalignant lesions and cancer, and is involved in carcinogenesis, tumor growth, and metastatic spread. Preclinical studies provided solid evidence that inhibition of this enzyme with selective COX-2 inhibitors prevents carcinogenesis, slows the growth of established tumors, and enhances tumor response to radiation without appreciably affecting normal tissue radioresponse. The mechanisms of enhancement of tumor radioresponse involve direct actions on tumor cells and indirect actions, primarily on tumor vasculature. COX-2 inhibitors also improve tumor response to chemotherapeutic agents, including irinotecan. Additional therapeutic benefit was observed for celecoxib (Celebrex), a selective COX-2 inhibitor, consisting of a strong reduction in irinotecan-induced diarrhea. Thus, selective targeting of COX-2 may potentially improve radiotherapy, chemotherapy, or chemoradiotherapy--a therapeutic strategy that is currently being tested in clinical trials.