Saleh M, Wiegmans A, Malone Q, Stylli S S, Kaye A H
The Department of Surgery, The University of Melbourne, and The Royal Melbourne Hospital, Parkville, Victoria, Australia.
J Natl Cancer Inst. 1999 Mar 3;91(5):438-45. doi: 10.1093/jnci/91.5.438.
Current therapies for malignant gliomas remain largely ineffective. We have previously demonstrated that interleukin 4 (IL-4) exhibits antitumorigenic activity in athymic nude mice by promoting both eosinophil infiltration and inhibition of tumor angiogenesis (formation of new blood vessels). In this study, we investigated treatment of established rat C6 cell gliomas by retroviral delivery of IL-4 in situ.
Tumors grown subcutaneously in athymic nude mice or implanted intracranially in immunocompetent Wistar rats were implanted with ecotropic retrovirus (i.e., will replicate only in cells of closely related species) packaging cells (RPCs) that were transfected with a retroviral vector encoding mouse IL-4 (1C5 cells) or a control vector (SV cells). For the demonstration of the long-term effects of such treatment, C6 cells were also implanted into the contralateral hemisphere of the brains of rats previously treated with 1C5 RPCs. Tumor volume measurements and immunohistochemical analyses were performed.
Implantation of 1C5 RPCs into subcutaneous C6 cell tumors resulted in tumor growth arrest that was associated with eosinophil infiltration and inhibition of angiogenesis. When 1C5 RPCs were stereotactically implanted into established intracranial tumors in rats, tumor volumes were dramatically smaller than in control animals (approximately 1.8 mm3 versus 70-80 mm3, respectively) 7 days after treatment. All 1C5 RPC-treated rats survived to 106 days after C6 cell implantation (99 days after treatment; an arbitrary end point), whereas control rats had to be killed 14 days after C6 cell implantation because of extensive tumor growth. Histologic analysis demonstrated that treated tumors were completely eradicated, and immunohistochemical analysis revealed an inhibition of tumor angiogenesis and infiltration by CD8+ cells and macrophages. C6 cells implanted contralaterally into the brains of long-term-surviving rats treated with 1C5 RPCs were also rapidly and completely rejected.
Implantation of packaging cells producing IL-4 retrovirus leads to rapid eradication of rat C6 cell gliomas and provides sustained protection against further intracranial challenge.
目前针对恶性胶质瘤的治疗方法大多无效。我们之前已经证明，白细胞介素4（IL-4）通过促进嗜酸性粒细胞浸润和抑制肿瘤血管生成（新血管形成），在无胸腺裸鼠中表现出抗肿瘤活性。在本研究中，我们研究了通过逆转录病毒原位递送IL-4来治疗已建立的大鼠C6细胞胶质瘤。
将在无胸腺裸鼠皮下生长或植入免疫活性Wistar大鼠颅内的肿瘤，植入用编码小鼠IL-4的逆转录病毒载体（1C5细胞）或对照载体（SV细胞）转染的嗜亲性逆转录病毒（即仅在密切相关物种的细胞中复制）包装细胞（RPC）。为了证明这种治疗的长期效果，还将C6细胞植入先前用1C5 RPC治疗的大鼠大脑的对侧半球。进行肿瘤体积测量和免疫组织化学分析。
将1C5 RPC植入皮下C6细胞肿瘤导致肿瘤生长停滞，这与嗜酸性粒细胞浸润和血管生成抑制有关。当将1C5 RPC立体定向植入大鼠已建立的颅内肿瘤中时，治疗7天后肿瘤体积比对照动物显著更小（分别约为1.8立方毫米对70 - 80立方毫米）。所有接受1C5 RPC治疗的大鼠在C6细胞植入后存活至106天（治疗后99天；一个任意终点），而对照大鼠由于肿瘤广泛生长在C6细胞植入后14天不得不被处死。组织学分析表明治疗后的肿瘤被完全根除，免疫组织化学分析显示肿瘤血管生成受到抑制，并且CD8 +细胞和巨噬细胞浸润。植入先前用1C5 RPC治疗的长期存活大鼠大脑对侧的C6细胞也迅速且完全被排斥。
植入产生IL-4逆转录病毒的包装细胞可导致大鼠C6细胞胶质瘤迅速根除，并提供针对进一步颅内攻击的持续保护。
