Kemper E M, Leenders W, Küsters B, Lyons S, Buckle T, Heerschap A, Boogerd W, Beijnen J H, van Tellingen O
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Eur J Cancer. 2006 Dec;42(18):3294-303. doi: 10.1016/j.ejca.2006.07.013. Epub 2006 Oct 5.
The blood-brain barrier (BBB) is considered one of the major causes for the low efficacy of cytotoxic compounds against primary brain tumours. The aim of this study was to develop intracranial tumour models in mice featuring intact or locally disrupted BBB properties, which can be used in testing chemotherapy against brain tumours. These tumours were established by intracranial injection of suspensions of different tumour cell lines. All cell lines had been transfected with luciferase to allow non-invasive imaging of tumour development using a super-cooled CCD-camera. Following their implantation, tumours developed which displayed the infiltrative, invasive or expansive growth patterns that are also found in primary brain cancer or brain metastases. Contrast-enhanced magnetic resonance imaging showed that the Mel57, K1735Br2 and RG-2 lesions grow without disruption of the BBB, whereas the BBB was leaky in the U87MG and VEGF-A-transfected Mel57 lesions. This was confirmed by immunohistochemistry. Bioluminescence measurements allowed the visualisation of tumour burden already within 4 days after injection of the tumour cells. The applicability of our models for performing efficacy studies was demonstrated in an experiment using temozolomide as study drug. In conclusion, we have developed experimental brain tumour models with partly disrupted, or completely intact BBB properties. In vivo imaging by luciferase allows convenient follow-up of tumour growth and these models will be useful for chemotherapeutic intervention studies.
血脑屏障（BBB）被认为是细胞毒性化合物对原发性脑肿瘤疗效欠佳的主要原因之一。本研究的目的是在小鼠中建立具有完整或局部破坏的血脑屏障特性的颅内肿瘤模型，可用于测试针对脑肿瘤的化疗。这些肿瘤通过颅内注射不同肿瘤细胞系的悬浮液来建立。所有细胞系均已转染荧光素酶，以便使用超低温电荷耦合器件相机对肿瘤发展进行非侵入性成像。植入后，肿瘤生长并呈现出原发性脑癌或脑转移瘤中也可见的浸润性、侵袭性或扩展性生长模式。对比增强磁共振成像显示，Mel57、K1735Br2和RG-2病变在血脑屏障未被破坏的情况下生长，而U87MG和转染VEGF-A的Mel57病变中的血脑屏障有渗漏。免疫组织化学证实了这一点。生物发光测量使得在注射肿瘤细胞后4天内就能可视化肿瘤负荷。在使用替莫唑胺作为研究药物的实验中，证明了我们的模型在进行疗效研究方面的适用性。总之，我们已经开发出了具有部分破坏或完全完整的血脑屏障特性的实验性脑肿瘤模型。通过荧光素酶进行的体内成像便于对肿瘤生长进行随访，这些模型将有助于化疗干预研究。
