Lee Intae, Shogen Kuslima
Department of Radiology, University of Pennsylvania, B6 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6069, USA.
Cancer Chemother Pharmacol. 2008 Jul;62(2):337-46. doi: 10.1007/s00280-007-0637-y. Epub 2007 Dec 5.
The effect of multiple small dosages of the cytotoxic RNase, ranpirnase (ONCONASE, ONC), on lung cancer was studied. The possible mechanisms for the enhanced tumoricidal efficacy of multiple small dosages of ONC were also investigated.
Hematoxylin and eosin staining, TUNEL labeling, 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 small and multiple dosages of ONC in vivo. ONC-induced changes in blood flow in A549 tumors and the kidney were measured non-invasively by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).
In cell culture studies, ONC significantly inhibited tumor growth of A549 human NSCLC cells without damaging non-cancerous cells (HLF-1 human lung fibroblast). Multiple small dosages of ONC significantly prolonged tumor growth delay of A549 tumors, with increased apoptosis in vivo from 0.5 +/- 0.3 to 70.1 +/- 1.1% (by TUNEL labeling, N = 3, P < 0.05). Interestingly, multiple small doses of ONC were more effective than a single large dose for the inhibition of tumor growth with reduced side effect. Using non-invasive DCE-MRI methods, we found that the mean of the K (trans) median values increased to 49.3 +/- 7.5% from the pre-ONC values by ONC (N = 4 mice, P < 0.05). A subsequent T (1) map of the kidney showed that T (1) values were temporarily decreased for up to 2 days (however, fully recovered approximately 4 days post-treatment).
Multiple small dosages of ONC significantly inhibited tumor growth of A549 NSCLC cells in vivo, with markedly increased apoptosis. This investigation suggests important potential clinical uses of ONC for the treatment of NSCLC cancer patients.
研究细胞毒性核糖核酸酶兰瑞肽酶（ONCONASE，ONC）多次小剂量给药对肺癌的影响。同时也探讨了多次小剂量ONC增强杀瘤效果的可能机制。
采用苏木精-伊红染色、TUNEL标记和半胱天冬酶-3抗体标记对细胞凋亡进行体内分析。应用生长延迟试验检测小剂量和多次剂量ONC在体内的治疗潜力。通过动态对比增强磁共振成像（DCE-MRI）无创测量ONC诱导的A549肿瘤和肾脏血流变化。
在细胞培养研究中，ONC显著抑制A549人非小细胞肺癌细胞的肿瘤生长，而不损伤非癌细胞（HLF-1人肺成纤维细胞）。多次小剂量ONC显著延长A549肿瘤的生长延迟，体内凋亡率从0.5±0.3%增加到70.1±1.1%（通过TUNEL标记，N = 3，P < 0.05）。有趣的是，多次小剂量ONC在抑制肿瘤生长方面比单次大剂量更有效，且副作用更小。使用无创DCE-MRI方法，我们发现K（trans）中位数平均值比ONC给药前的值增加到49.3±7.5%（N = 4只小鼠，P < 0.05）。随后的肾脏T（1）图显示，T（1）值暂时降低长达2天（然而，在治疗后约4天完全恢复）。
多次小剂量ONC在体内显著抑制A549非小细胞肺癌细胞的肿瘤生长，凋亡明显增加。本研究表明ONC在治疗非小细胞肺癌患者方面具有重要的潜在临床应用价值。
