In light of the current state of heightened terrorism risk, rapidly accessible and easily distributed countermeasures are urgently required as mitigators following a mass radiological or nuclear event. Since our increased ability to care for victims of acute accidental (or intentional) exposure means that exposed persons are more likely to survive the immediate hematological crises which result from whole body exposure, nonetheless late morbidities will still occur as part of a multi-organ dysfunction syndrome. Therefore, the downstream roles played by such organs as the lung in this syndrome's progression are of increasing concern. Although the overall progression to pulmonary late effects (pneumonitis and fibrosis) is well recognized, the complex nature of the pathways leading to their development, which includes cellular, molecular and temporal components, has led to our group's contention that no single agent or strategy is likely to be an effective mitigator or treatment against these potentially lethal endpoints. We have therefore devised a systematic experimental design, using a pertinent """"""""2-strain"""""""" murine model, in which we will assess combination therapies that include a broad-based anti-inflammatory together with a number of alternative agents, each of which has been chosen for its known target within the pulmonary late effect progression. In addition, these combinations will be assessed in terms of an acute versus a chronic treatment approach. We anticipate that by the end of the funding period, we will have identified one or more combination therapies, each with defined dosing approaches, that could potentially be developed for use in both the immediate and delayed periods following a radiological event.
This proposal has relevance in two of the developmental areas supported by this RFA. By the end of the funding period, we will have established the efficacy of agents that may be used during both the acute and chronic phases of the pulmonary sequelae to radiation and, also, will have defined the optimal drug combinations and optimal time periods for their use during the development and progression of pulmonary late effects.
| Williams, Jacqueline P; Calvi, Laura; Chakkalakal, Joe V et al. (2016) Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury. Radiat Res 186:1-16 |
| Williams, Jacqueline P; Johnston, Carl J; Finkelstein, Jacob N (2010) Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr Drug Targets 11:1386-94 |
| Bentzen, Soren M; Parliament, Matthew; Deasy, Joseph O et al. (2010) Biomarkers and surrogate endpoints for normal-tissue effects of radiation therapy: the importance of dose-volume effects. Int J Radiat Oncol Biol Phys 76:S145-50 |
