title: The therapeutic mechanisms of ranpirnase-induced enhancement of radiation response on A549 human lung cancer.
abstract: OBJECTIVE
  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.
  
  
  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 noninvasive 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 microg/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 approximately 20% decrease in lactate levels with ONC was found.
  
  
  CONCLUSIONS
  ONC may be a new and promising drug in the treatment of NSCLC as a radiation therapy enhancer.
authors.affiliation: Department of Radiology, University of Pennsylvania, B6 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6069, USA. intaelee@gmail.com
authors.forename: Intae
authors.initials: I
authors.lastname: Lee
authors.forename: Dae H
authors.initials: DH
authors.lastname: Kim
authors.forename: Ulas
authors.initials: U
authors.lastname: Sunar
authors.forename: Sergey
authors.initials: S
authors.lastname: Magnitsky
authors.forename: Kuslima
authors.initials: K
authors.lastname: Shogen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D012260:Ribonucleases / Q000494:pharmacology* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D012260:Ribonucleases; C058703:ranpirnase