Ichikura Haruhiko, Eto Masatoshi, Ueno Hikaru, Harada Mamoru, Takayama Koichi, Tokuda Noriaki, Tatsugami Katsunori, Naito Seiji
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka 812-8582, Japan.
Oncol Rep. 2006 May;15(5):1333-7.
Antiangiogenic therapy is a promising strategy for the treatment of cancer since tumor development and metastases require angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most important factors in tumor angiogenesis. In the present study, we investigated the antitumor effect of an adenovirus (AdVEGF-ExR) expressing the extracellular domain of the human VEGF receptor (flt-1) using two different urological tumor/mouse systems. RENCA, a renal cell carcinoma of BALB/c origin, and MBT-2, a poorly differentiated transitional carcinoma of C3H/He origin, were used. Both types of tumor were in vitro infected with AdVEGF-ExR and inoculated subcutaneously into the abdomens of syngenenic mice, and tumor growth was measured twice weekly. In some experiments, BALB/c mice with established RENCA tumors were injected intramuscularly with AdVEGF-ExR as a therapeutic model. The cytotoxicity of spleen cells from the tumor-rejected mice was assessed by 51Cr-release assay. Although the in vitro cell growth of either MBT-2 or RENCA was not affected by infection with AdVEGF-ExR, the in vivo growth of both AdVEGF-ExR-infected tumors was significantly suppressed in the syngeneic mice. In addition, although 2 of 5 mice rejected the AdVEGF-ExR-infected RENCA, tumor-specific cytotoxic T lymphocytes were not generated from their spleen cells, thus suggesting no cellular immune response. In a therapeutic model, intramuscular injections of AdVEGF-ExR at a remote site also significantly suppressed the growth of the subcutaneously established RENCA. These results indicate that the adenovirus-mediated expression of a soluble VEGF receptor can be an effective therapy for urological cancer treatment; however, such VEGF-targeted gene therapy is not necessarily accompanied by subsequent antitumor T cell immunity.
抗血管生成疗法是一种很有前景的癌症治疗策略，因为肿瘤的发展和转移需要血管生成。血管内皮生长因子（VEGF）是肿瘤血管生成中最重要的因子之一。在本研究中，我们使用两种不同的泌尿系统肿瘤/小鼠模型系统，研究了表达人VEGF受体（flt-1）细胞外结构域的腺病毒（AdVEGF-ExR）的抗肿瘤作用。使用了源自BALB/c的肾细胞癌RENCA和源自C3H/He的低分化移行癌MBT-2。将两种肿瘤细胞在体外感染AdVEGF-ExR，然后皮下接种到同基因小鼠的腹部，每周两次测量肿瘤生长情况。在一些实验中，将患有已形成RENCA肿瘤的BALB/c小鼠肌肉注射AdVEGF-ExR作为治疗模型。通过51Cr释放试验评估肿瘤排斥小鼠脾细胞的细胞毒性。虽然AdVEGF-ExR感染对MBT-2或RENCA的体外细胞生长没有影响，但在同基因小鼠中，两种AdVEGF-ExR感染肿瘤的体内生长均受到显著抑制。此外，虽然5只小鼠中有2只排斥AdVEGF-ExR感染的RENCA，但从它们的脾细胞中未产生肿瘤特异性细胞毒性T淋巴细胞，因此表明没有细胞免疫反应。在治疗模型中，在远处肌肉注射AdVEGF-ExR也显著抑制了皮下形成的RENCA的生长。这些结果表明，腺病毒介导的可溶性VEGF受体表达可以成为泌尿系统癌症治疗的有效方法；然而，这种VEGF靶向基因治疗不一定会伴随随后的抗肿瘤T细胞免疫反应。
