The therapeutic mechanisms of ranpirnase-induced enhancement of radiation response on A549 human lung cancer

Aim: The goal of this study was to investigate the therapeutic potential of combining radiation therapy and cytotoxic RNase, ranpirnase (ONCONASE®; ONC), in human lung tumor models in vitro and in vivo. As translational implications, the non-invasive monitoring response to individual therapy with ONC was also investigated to determine the underlying therapeutic mechanisms. Materials and Methods: A clonogenic survival assay was used to measure the effect of ONC and radiation on A549 human non-small cell lung carcinoma (NSCLC) cells. H&E staining, TUNEL staining and caspase-3-antibody labeling were used for in vivo analysis of apoptosis. A growth-delay assay was applied to detect the therapeutic potential of ONC as a radiation sensitizer in vivo. ONC-induced changes in blood flow and biochemical metabolites were measured by various non-invasive dynamic contrast enhanced magnetic resonance imaging (DCE MRI), non-localized ¹H magnetic resonance spectroscopy (MRS), and near-infrared spectroscopy (NIRS) methods. Results: ONC at 5-10 μg/ml sensitized the radiation response of A549 tumor cells in vitro. Remarkable increases in ONC-induced apoptosis in vivo were observed in caspase-3 antibody labeling and TUNEL staining assays. ONC significantly increased the radiation-induced tumor growth delay of A549 tumors. It was observed, when using a DCE MRI method, that there were significant increases in K^trans values at the rim of tumor regions at 1.5 h post-injection of ONC. When using non-localized ¹H MRS, an ∼ 20% decrease in lactate levels with ONC was found. Conclusion: ONC may be a new and promising drug in the treatment of NSCLC as a radiation therapy enhancer.