Effects of Nsaids on Radiation-Induced Pulmonary Responses

Lung has been long recognized as a dose-limiting structure in the radiotherapy (RT)of thoracic tumor and in the total-body irradiation(TBI) for bone marrow trasplantation. Its high radiosensitivity has been clearly underlined by the high incidnce of interstitial pneumonitis after a single, large fraction TBI in human and lethal pneumonitis was induced in animals following whole lung irradiation in the dose range of sub-lethal to other organs. There is a need to identify novel ways to increase the effectiveness of this front-line therapy for cancer and decrease the pulmonary damages. We recently characterized radiation-induced pulmonary responses in murine lung and found there was a cascade of pro-inflammatory cytokin gene overexpression and inflammatory cell infiltration following thoracic irradiation(IR), which contribute to complications such as radiation pneumonitis and/or fibrosis. In this project, we will move forward and try to manipulate the radiation response in lung by drug. we propose to use an animal model to test if Non-steroid Anti-inflammatory Drugs(NSAIDs) could be used in vivo to prevent and inhibit radiation pneumonitis and to enhance tumor control in lung following irrafdiation(IR). In addition, NSAIDs including aspirin, indomethacin and ibuprofen, which gain the most therapeutic ratio to achieve this goal, will be identified. The finding from this project will become our pre-clinical basis in human trials of combination of NSAIDs and IR in the treatment of thoracic tumor. The hypotheses we are going to test are (1).At least one of NSAIDs, aspirin, indomethacin and ibuprofen, is an effective drug to inhibit or prevent radiation pneumonitis. (2).The inflammatory and other reponses following IR will affect tumor growth and metastasis, which could be modified by NSAIDs. (3).Use of NSAIDs will enhance tumor control by IR. We will use C3H/HeN mice as our animal model because they are genetically prone to develop radiation pneumonitis and their pulmonary responses to IR has been well established in our hand. Our previous finding in this strain of mice are the basis for evaluation of drug effects in this renew project. In addition to the methods have been established by us for studying normal tissue reponses, we are going to set up new tumor models to evaluate the effect of drugs for tumor. Our specific aims are: 1.To investigate the effects of aspirin, indomethacin and ibuprofen on radiation-induced pro-inflammatory responses in lung and identify drugs with greatest efficacy. 2.To investigate the effects of radiation-induced pulmonary responses on metastasis and growth of tumor in an artificial metastasis model. 3.To investigate the effects of NSAIDs on the tumor metastasis and growth in the irradiated and un-irradiated lung. 4.To investigate if NSAIDs can inhibit tumor growth and enhance tumor killing by radiation.

Project ID:PG9102-0349
External Project ID:NHRI-EX91-9030SL