PROCCA: early and late effects after X-irradiation of the head and neck region
Purpose: Damage to normal tissue following radiotherapy of head and neck (H&N) cancers causes severe early and late effects (salivary hypofunction, oral mucositis, and skin toxicity) and reduction in quality of life. This may lead to unplanned interruptions in treatment, and potentially treatment failure. Side effects are well documented for conventional X-ray therapy, however, important questions regarding the mechanisms and cellular signaling pathways culminating in this damage remain unanswered. Knowledge of these mechanisms is vital for early detection of patients at risk and the development of strategies for mitigation. Such studies are not possible in human patients, and we therefore require the use of animals. The purpose of the study is to establish a preclinical model for radiation-induced effects in the H&N region.
Distress: Irradiated animals are expected to experience acute erythema/edema/desquamation of lips, inflammation/ulceration of skin/oral mucosa, fur loss in the field of irradiation. However, acute effects are expected to partially resolve in the weeks following irradiation.
Expected benefit: At present there is no established preclinical model to research radiation-induced effects in H&N region. In addition, there are many ambiguities in the descriptions of the appearance of these effects. Based on our results from two pilots on early (ID 26246) and late effects (ID 20889) we created the score scheme that covers all the effects that might be seen after local irradiation of H&N region in the relevant mouse strain. The experience and data obtained during the two pilots allowed us to refine all the protocols and create an optimal experimental design including the follow-up investigations. Moreover, we found that the particular mouse strain used develops mild symptoms after irradiation, which indicates that the applied radiation doses were too low to induce clinical effects. We will therefore increase radiation doses and include an additional radiation schemes. This study will use both a single and fractionated radiotherapy design to investigate the mechanisms of radiation-induced damage of normal tissues in the H&N region and to compare fractionated and single-dose irradiation. Both early and late effects after radiation will be studied. For three groups of animals, we want to test if injections with transforming growth factor beta 3 (TGF-b3), which has previously been seen to alleviate fibrosis, can reduce the side effects of radiation. Blood and saliva sampling will be performed for further cytokine screening in order to explore potential toxicity biomarkers. A subset of animals will be examined by magnetic resonance imaging.
Number of animals: We apply for a total of 131 C57BL/6 mice.
How to adhere to 3R: Clinical symptoms in the skin and oral cavity will be monitored and scored by frequent oral examinations. Animal welfare will be ensured through close monitoring during and post radiotherapy, with strict compliance with humane endpoints. Analgesia and alternative fodder will be provided to alleviate symptoms and ease feeding/maximize nutrition. The design of the experiment allows combining two different projects and using mice from the radiation groups as control for mice with TGF-b3 injection as a way of reducing the number of animals.
Distress: Irradiated animals are expected to experience acute erythema/edema/desquamation of lips, inflammation/ulceration of skin/oral mucosa, fur loss in the field of irradiation. However, acute effects are expected to partially resolve in the weeks following irradiation.
Expected benefit: At present there is no established preclinical model to research radiation-induced effects in H&N region. In addition, there are many ambiguities in the descriptions of the appearance of these effects. Based on our results from two pilots on early (ID 26246) and late effects (ID 20889) we created the score scheme that covers all the effects that might be seen after local irradiation of H&N region in the relevant mouse strain. The experience and data obtained during the two pilots allowed us to refine all the protocols and create an optimal experimental design including the follow-up investigations. Moreover, we found that the particular mouse strain used develops mild symptoms after irradiation, which indicates that the applied radiation doses were too low to induce clinical effects. We will therefore increase radiation doses and include an additional radiation schemes. This study will use both a single and fractionated radiotherapy design to investigate the mechanisms of radiation-induced damage of normal tissues in the H&N region and to compare fractionated and single-dose irradiation. Both early and late effects after radiation will be studied. For three groups of animals, we want to test if injections with transforming growth factor beta 3 (TGF-b3), which has previously been seen to alleviate fibrosis, can reduce the side effects of radiation. Blood and saliva sampling will be performed for further cytokine screening in order to explore potential toxicity biomarkers. A subset of animals will be examined by magnetic resonance imaging.
Number of animals: We apply for a total of 131 C57BL/6 mice.
How to adhere to 3R: Clinical symptoms in the skin and oral cavity will be monitored and scored by frequent oral examinations. Animal welfare will be ensured through close monitoring during and post radiotherapy, with strict compliance with humane endpoints. Analgesia and alternative fodder will be provided to alleviate symptoms and ease feeding/maximize nutrition. The design of the experiment allows combining two different projects and using mice from the radiation groups as control for mice with TGF-b3 injection as a way of reducing the number of animals.