Heckler Max, Osterberg Nadja, Guenzle Jessica, Thiede-Stan Nina Kristin, Reichardt Wilfried, Weidensteiner Claudia, Saavedra Joseph E, Weyerbrock Astrid
1 Department of Neurosurgery, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2 Faculty of Biology, University of Freiburg, Freiburg, Germany.
Tumour Biol. 2017 Jun;39(6):1010428317703922. doi: 10.1177/1010428317703922.
As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S-transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death. In vivo efficacy of JS-K and repetitive irradiation were investigated in an orthotopic U87 xenograft model in mice. For the first time, we could show that JS-K acts as a potent cytotoxic and radiosensitizing agent in U87 cells in vitro. This dose- and time-dependent effect is due to an enhanced induction of DNA double-strand breaks leading to mitotic catastrophe as the dominant form of cell death. However, this potent cytotoxic and radiosensitizing effect could not be confirmed in an intracranial U87 xenograft model, possibly due to insufficient delivery into the brain. Although NO donor treatment was well tolerated, neither a retardation of tumor growth nor an extended survival could be observed after JS-K and/or radiotherapy.
作为一种有效的放射增敏剂，一氧化氮（NO）可能是治疗恶性胶质瘤的一种潜在佐剂，恶性胶质瘤以其放射和化学抗性而闻名。NO供体前药JS-K（O2-(2,4-二硝基苯基)-1-[(4-乙氧羰基)哌嗪-1-基]重氮-1,2-二醇盐）可通过多形性胶质母细胞瘤中过表达的谷胱甘肽-S-转移酶进行酶促活化，实现细胞类型特异性的细胞内NO释放。在体外U87胶质瘤细胞中评估了JS-K的细胞毒性和放射增敏效果，重点关注细胞增殖、DNA损伤诱导和细胞死亡。在小鼠原位U87异种移植模型中研究了JS-K和重复照射的体内疗效。首次发现，JS-K在体外U87细胞中作为一种有效的细胞毒性和放射增敏剂发挥作用。这种剂量和时间依赖性效应是由于DNA双链断裂的诱导增强，导致有丝分裂灾难成为细胞死亡的主要形式。然而，在颅内U87异种移植模型中未能证实这种强大的细胞毒性和放射增敏作用，可能是由于向脑内的递送不足。尽管NO供体治疗耐受性良好，但在JS-K和/或放疗后，既未观察到肿瘤生长延迟，也未观察到生存期延长。
