Radioprotective Agents in NSCLC Therapy

Effective treatment of many lung cancers encompasses the triad of surgery, chemotherapy and irradiation. However, the effectiveness of both chemotherapy and irradiation is limited by local and systemic toxicity against healthy tissues due to the production of free radicals. To counter these undesirable effects, extensive efforts have been directed at the development of cytoprotective agents capable of preserving normal cells without inhibiting the cytotoxic activity of these therapeutic agents. The only approved agent effective in reducing the untoward side effects of chemotherapy in lung cancer patients is Amifostine, i.e. Ethoyl, WR-2721. It is primarily a scavenger of free radicals. The goal of our research is to develop a new generation of therapeutic agents that are both radioprotective for healthy tissue and cytotoxic for tumor tissue. Recently, we have identified the compound D609 as being both radioprotective and tumor toxic. The combination of in vivo irradiation and D609 therapy exhibits synergy yielding longer leukemia free survival in our A20 murine leukemia model system. Thus, D609 protects the normal host tissue while being cytotoxic for the tumor cells. Our goal in this pre-clinical study is to develop D609 as a radioprotective-tumor toxic agent for the therapy of lung cancer. Specifically, we will test the hypothesis that the radioprotective agent D609 is toxic for lung cancer cells while protecting normal cells. In turn, this radioprotection will preserve host lung immune function and increase resistance to Pneumocystis carin;; lung infection following radiation therapy. These studies will use the murine non small cell lung carcinoma (NSCLC) Lewis lung cancer model. Specifically, we will investigate the following specific aims: Aim One: To determine the cytotoxicity profile of D609 and D609 plus irradiation for murine Lewis lung cancer cells in vitro. Aim Two: To determine in vivo if D609 is radioprotective for normal lung and esophegial tissue as well as host lung immune function and resistance to infection. Aim Three: To determine ifD609 increases survival and the efficacy of irradiation therapy in the murine Lewis lung cancer cell model. In all studies, the effectiveness of D609 will be compared to Amifostine. We expect that the combination of radioprotection and tumor toxicity offered by D609 will result in more effective therapy for lung cancer.