van Herpen Carla M L, Bussink Johan, van der Kogel Albert J, Peeters Wenny J M, van der Voort Robbert, van Schijndel Anita, de Wilde Peter C M, Adema Gosse J, de Mulder Pieter H M
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, The Netherlands.
Anticancer Res. 2005 Mar-Apr;25(2A):1015-21.
Interleukin-12 is an anti-angiogenic and antitumor agent in many transplanted murine tumour models. In a previous clinical study in head and neck squamous cell carcinoma patients treated with rhIL-12 the tumour turned pale, after an initial reddening. The aim of this study was to investigate the effects of rmIL-12 on the vasculature, blood perfusion, hypoxia and proliferation of tumour cells in an implanted human head and neck squamous cell carcinoma xenograft tumour, with a relatively large diameter, in Balb/c nu/nu mice over time.
Established human squamous cell carcinoma xenograft tumours were intratumorally injected for 3 days with either 200 ng rmIL-12 or PBA. Mice were sacrificed at 4 different time points (between 8 hours and 8 days after the last injection), after administration of Pimonidazole, BrdUrd and Hoechst 33342. The tumour sections were quantitatively analysed with a semi-automatic method based on a computerised digital image analysis system, after immunohistochemical staining.
Despite a faster and higher up-regulation of anti-mouse ICAM-1 in the IL-12-treated tumours, no significant differences in vascular density, perfusion fraction, hypoxic fraction and BrdUrd labelling index were detected between IL-12-treated tumour and control tumours.
We suggest that the main reason why the observation made in humans could not be confirmed in this mice study is the combination of a lack of an intact immune system in the Balb/c nu/nu mice and a relatively large tumour with probably a lot of mature vessels.
在许多移植的小鼠肿瘤模型中，白细胞介素-12是一种抗血管生成和抗肿瘤剂。在先前一项针对接受重组人白细胞介素-12治疗的头颈部鳞状细胞癌患者的临床研究中，肿瘤在最初变红后变白。本研究的目的是随着时间推移，研究重组小鼠白细胞介素-12对Balb/c裸鼠体内植入的相对大直径的人源头颈部鳞状细胞癌异种移植瘤的脉管系统、血液灌注、缺氧情况及肿瘤细胞增殖的影响。
已建立的人鳞状细胞癌异种移植瘤瘤内注射200 ng重组小鼠白细胞介素-12或磷酸缓冲液，持续3天。在注射匹莫硝唑、溴脱氧尿苷和Hoechst 33342后，于4个不同时间点（最后一次注射后8小时至8天之间）处死小鼠。免疫组织化学染色后，基于计算机数字图像分析系统采用半自动方法对肿瘤切片进行定量分析。
尽管白细胞介素-12治疗组肿瘤中抗小鼠细胞间黏附分子-1的上调更快且更高，但在白细胞介素-12治疗组肿瘤与对照组肿瘤之间，未检测到血管密度、灌注分数、缺氧分数及溴脱氧尿苷标记指数的显著差异。
我们认为在本小鼠研究中未能证实人类观察结果的主要原因是Balb/c裸鼠缺乏完整的免疫系统以及相对较大的肿瘤可能有许多成熟血管这两者的结合。
