Lee Intae, Kim Dae H, Sunar Ulas, Magnitsky Sergey, Shogen Kuslima
Department of Radiology, University of Pennsylvania, B6 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6069, USA.
In Vivo. 2007 Sep-Oct;21(5):721-8.
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.
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.
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.
ONC may be a new and promising drug in the treatment of NSCLC as a radiation therapy enhancer.
本研究的目的是在体外和体内人肺肿瘤模型中研究放射治疗与细胞毒性核糖核酸酶兰瑞肽酶（ONCONASE；ONC）联合使用的治疗潜力。作为转化意义，还研究了对ONC个体治疗的非侵入性监测反应，以确定潜在的治疗机制。
采用克隆形成存活试验来测量ONC和放射对A549人非小细胞肺癌（NSCLC）细胞的影响。苏木精-伊红（H&E）染色、末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色和半胱天冬酶-3抗体标记用于体内凋亡分析。应用生长延迟试验来检测ONC作为体内放射增敏剂的治疗潜力。通过各种非侵入性动态对比增强磁共振成像（DCE MRI）、非定位氢磁共振波谱（MRS）和近红外光谱（NIRS）方法测量ONC诱导的血流和生化代谢物变化。
5-10微克/毫升的ONC在体外使A549肿瘤细胞的放射反应敏感化。在半胱天冬酶-3抗体标记和TUNEL染色试验中观察到体内ONC诱导的凋亡显著增加。ONC显著增加了A549肿瘤的放射诱导肿瘤生长延迟。当使用DCE MRI方法时，在注射ONC后1.5小时，肿瘤区域边缘的转运常数（K(trans)）值显著增加。当使用非定位氢MRS时，发现ONC使乳酸水平降低约20%。
作为放射治疗增强剂，ONC可能是治疗NSCLC的一种新的有前景的药物。
