Potential for combined modality therapy of cyclooxygenase inhibitors and radiation.

In conclusion, COX-2 inhibitors have potent anti-tumorigenic activity. Results from animal studies strongly indicate that the likely mechanism for enhanced TGD and TCD50 in tumors treated with radiation and COX-2 inhibitors was the inhibition of angiogenesis. In our recent findings we observed that the antagonists of angiogenesis also inhibited the endogenous as well as phorbol-ester-mediated induction of COX-2 expression in human lung cancer cell lines and that in the xenograft model a combination of angiogenic antagonists and radiation significantly delayed tumor growth [ASCO 2002, Vol. 21 (Part 1); p445a, #1779]. In human tumor models, apoptosis was another mechanism of cell death. Furthermore, it was demonstrated that COX-2 inhibitors could change the intrinsic radiosensitivity of human cancer cells [41]. Therefore, inhibition of angiogenesis by COX-2 inhibitors may be the major mechanism for increased radiation effects in tumors. However, other mechanisms such as changes in tumor perfusion, apoptosis, and an increase in intrinsic radiation sensitivity must also be considered. Inhibitors of COX-2 in combination with radiation therapy may be an alternative strategy that can be tested in clinical trials. The combination of COX-2 inhibitors and radiation suggest a complementary strategy to target angiogenesis while potentially minimizing the impact on quality of life. Currently, the Radiation Therapy Oncology Group [www.rtog.org] is just one of the National Cancer Institute sponsored cooperative groups conducting clinical trials in cervix cancer, lung cancer and brain tumors, using inhibitors of COX-2 in combination with chemotherapy and radiation therapy. These clinical trials will help elucidate the role of this interesting class of agents in combination with cytotoxic therapy for the treatment of cancer.