Within this millennium there has been resurgence in funding and research dealing with animal models of radiationinduced lung injury to identify and establish predictive biomarkers and effective mitigating agents that are applicable to humans. Most have been performed on mice but there needs to be assurance that the emphasis on such models is not misplaced. We therefore considered it timely to perform a comprehensive appraisal of the literature dealing with radiation lung injury of mice and to critically evaluate the validity and clinical relevance of the research. A total of 357 research papers covering the period of 1970-2015 were extensively reviewed. Whole thorax irradiation (WTI) has become the most common treatment for studying lung injury in mice and distinct trends were seen with regard to the murine strain, radiation dose, intended pathology investigated, length of study, and assays. Recently, the C57BL/6 strain has been increasingly used in the majority of these studies with the notion that they are susceptible to pulmonary fibrosis. Nonetheless, many of these investigations depend on animal survival as the primary end point and neglect the importance of radiation pneumonitis and the anomaly of lethal pleural effusions. A relatively large variation in survival times of C5BL/6 mice is also seen among different institutions pointing to the need for standardization of radiation treatments and environmental conditions. An analysis of mitigating drug treatments is complicated by the fact that the majority of studies are limited to the C57BL/6 strain with a premature termination of the experiments and do not establish whether the treatment actually prevents or simply delays the progression of radiation injury. This survey of the literature has pointed to several improvements that need to be considered in establishing a reliable preclinical murine model of radiation lung injury. The lethality end point should also be used cautiously and with greater emphasis on other assays such as non-invasive lung functional and imaging monitoring in order to quantify specific pulmonary injury that can be better extrapolated to radiation toxicity encountered in our own species.Laboratory Investigation (2016) 96, 936-949;

No abstract

No abstract

Background and purpose: There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective. Materials and methods: We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and in vivo. Results: Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway. Conclusions: Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC.

Purpose: Glioblastoma (GBM) is a locally aggressive radioresistant brain tumor with poor prognosis. Previous preclinical studies using an intracranial model of GBM demonstrated Pulsed-RT (PRT)+ concomitant TMZ was a novel and effective first-line therapy. The aim of the current study was to evaluate if inhibitors of DNA base excision repair (BER) could further increase the efficacy of PRT+TMZ therapy for the treatment of GBM. The BER pathway is a major contributor to TMZ cellular resistance, so inhibition of this pathway could re-sensitize TMZ resistant tumors and improve radiation efficacy. Conclusion: BER inhibitors increased cell killing when RT was combined with TMZ, and were equally effective in the PRT and SRT-based combinations. CUR and DDN were the most effective BER inhibitors in vitro. In vivo, CUR alone was not effective at preventing tumor growth or improving survival. CUR increased the effectiveness of TMZ as determined by slower tumor growth rates, however all benefit was lost was 26 days post Tx. The data support the development of combinational regimes of BER inhibitors with RT+TMZ in an effort to improve patient outcomes.