ABSTRACT
BACKGROUND AND PURPOSE: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis. MATERIALS AND METHODS: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining. RESULTS: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p<0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p>0.5) and histological scoring of radiation induced fibrosis (p>0.5). CONCLUSION: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/radiotherapy , Lung Neoplasms/radiotherapy , Pyrimidines/pharmacology , Sulfoxides/pharmacology , Therapeutic Index , Animals , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Cell Line, Tumor , Cone-Beam Computed Tomography , Female , Humans , Indoles , Mice , Mice, Inbred C57BL , Morpholines , Sulfonamides , Xenograft Model Antitumor AssaysABSTRACT
Laminin-α2 related Congenital Muscular Dystrophy (LAMA2-CMD) is a progressive muscle disease caused by partial or complete deficiency of laminin-211, a skeletal muscle extracellular matrix protein. In the last decade, basic science research has queried underlying disease mechanisms in existing LAMA2-CMD murine models and identified possible clinical targets and pharmacological interventions. Experimental rigor in preclinical studies is critical to efficiently and accurately quantify both negative and positive results, degree of efficiency of potential therapeutics and determine whether to move a compound forward for additional preclinical testing. In this review, we compare published available data measured to assess three common parameters in the widely used mouse model DyW, that mimics LAMA2-CMD, we quantify variability and analyse its possible sources. Finally, on the basis of this analysis, we suggest standard set of assessments and the use of available standardized protocols, to reduce variability of outcomes in the future and to improve the value of preclinical research.
