The therapeutic mechanisms of ranpirnase-induced enhancement of radiation response on A549 human lung cancer.
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.
Lee
Intae
I
Department of Radiology, University of Pennsylvania, B6 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6069, USA. intaelee@gmail.com
Kim
Dae H
DH
Sunar
Ulas
U
Magnitsky
Sergey
S
Shogen
Kuslima
K
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
D012260:Ribonucleases; C058703:ranpirnase