Bakalova Rumiana, Zhelev Zhivko, Shibata Sayaka, Nikolova Biliana, Aoki Ichio, Higashi Tatsuya
Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences (NIRS), National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan
Medical Faculty, Sofia University "St. Kliment Ohridski", Sofia, Bulgaria.
Anticancer Res. 2017 Oct;37(10):5449-5458. doi: 10.21873/anticanres.11973.
BACKGROUND/AIM: The study aimed to investigate the effect of multi-targeted combinations (SN38/EF24; SN38/EF24/melatonin) on the growth of colon cancer in experimental animals and their impact on the ratio "oncogenic"/"onco-suppressive" reactive oxygen species (ROS) - a crucial factor for triggering carcinogenesis, as well as for development of effective therapeutic strategies.
The experiments were conducted on colon cancer-grafted mice - non-treated, SN38/EF24-treated and SN38/EF24/melatonin-treated within 22 days. The balance between different types of ROS was measured in vivo by nitroxide-enhanced magnetic resonance imaging (MRI), as well as on isolated tissue specimens by conventional analytical tests.
Both combinations significantly suppressed the tumor growth. Impressive anticancer effect was observed in SN38/EF24/melatonin-treated mice - almost complete destruction of the tumor. Both types of ROS (superoxide and hydroperoxides) were elevated in cancer, but the MRI data suggest that the ratio between them tends towards superoxide. SN38/EF24 decreased the level of superoxide, but did not affect the level of hydroperoxides in the cancerous tissue, while SN38/EF24/melatonin decreased the level of superoxide below the control and increased significantly the level of hydroperoxides.
The most important observations are that: (i) colon cancer was characterized by a vicious cycle, that ensures a permanent domination of "oncogenic" ROS (as superoxide) over "onco-suppressive" ROS (as hydrogen peroxide); (ii) the anticancer effect of the triple combination EF24/SN38/melatonin was accompanied by decreasing "oncogenic" and increasing "onco-suppressive" ROS; (iii) the ratio between both types of ROS could be a new onco-target for combined therapy; and (iv) nitroxide-enhanced MRI is a valuable tool for analyzing of this ratio.
背景/目的：本研究旨在探讨多靶点组合（SN38/EF24；SN38/EF24/褪黑素）对实验动物结肠癌生长的影响及其对“致癌性”/“抑癌性”活性氧（ROS）比例的影响——ROS是引发致癌作用以及制定有效治疗策略的关键因素。
实验在移植了结肠癌的小鼠身上进行，分为未治疗组、SN38/EF24治疗组和SN38/EF24/褪黑素治疗组，为期22天。通过氮氧化物增强磁共振成像（MRI）在体内测量不同类型ROS之间的平衡，并通过传统分析测试在分离的组织标本上进行测量。
两种组合均显著抑制肿瘤生长。在SN38/EF24/褪黑素治疗的小鼠中观察到了显著的抗癌效果——肿瘤几乎完全被破坏。两种类型的ROS（超氧化物和氢过氧化物）在癌症中均升高，但MRI数据表明它们之间的比例倾向于超氧化物。SN38/EF24降低了超氧化物水平，但不影响癌组织中氢过氧化物水平，而SN38/EF24/褪黑素使超氧化物水平降至对照组以下，并显著提高了氢过氧化物水平。
最重要的观察结果是：（i）结肠癌的特征是恶性循环，确保“致癌性”ROS（如超氧化物）对“抑癌性”ROS（如过氧化氢）的永久主导；（ii）三联组合EF24/SN38/褪黑素的抗癌作用伴随着“致癌性”ROS的降低和“抑癌性”ROS的增加；（iii）两种类型ROS之间的比例可能是联合治疗的新肿瘤靶点；（iv）氮氧化物增强MRI是分析该比例的有价值工具。
