Claes An, Wesseling Pieter, Jeuken Judith, Maass Cathy, Heerschap Arend, Leenders William P J
Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Mol Cancer Ther. 2008 Jan;7(1):71-8. doi: 10.1158/1535-7163.MCT-07-0552. Epub 2008 Jan 9.
Glioblastomas are highly aggressive primary brain tumors. Curative treatment by surgery and radiotherapy is generally impossible due to the presence of diffusely infiltrating tumor cells. Furthermore, the blood-brain barrier (BBB) in infiltrative tumor areas is largely intact, and this hampers chemotherapy as well. The occurrence of angiogenesis in these tumors makes these tumors attractive candidates for antiangiogenic therapies. Because antiangiogenic compounds have been shown to synergize with chemotherapeutic compounds in other tumor types, based on vessel normalization, there is a tendency toward such combination therapies for primary brain tumors also. However, vessel normalization in brain may result in restoration of the BBB with consequences for the efficacy of chemotherapeutic agents. In this study, we investigated this hypothesis. BALB/c nude mice with intracerebral xenografts of the human glioblastoma lines E98 or U87 were subjected to therapy with different dosages of vandetanib (an angiogenesis inhibitor), temozolomide (a DNA alkylating agent), or a combination (n>8 in each group). Vandetanib selectively inhibited angiogenic growth aspects of glioma and restored the BBB. It did not notably affect diffuse infiltrative growth and survival. Furthermore, vandetanib antagonized the effects of temozolomide presumably by restoration of the BBB and obstruction of chemodistribution to tumor cells. The tumor microenvironment is an extremely important determinant for the response to antiangiogenic therapy. Particularly in brain, antiangiogenic compounds may have adverse effects when combined with chemotherapy. Thus, use of such compounds in neuro-oncology should be reconsidered.
胶质母细胞瘤是极具侵袭性的原发性脑肿瘤。由于存在弥漫性浸润的肿瘤细胞，通过手术和放疗进行根治性治疗通常是不可能的。此外，浸润性肿瘤区域的血脑屏障（BBB）在很大程度上是完整的，这也阻碍了化疗。这些肿瘤中血管生成的发生使它们成为抗血管生成疗法的有吸引力的候选对象。因为抗血管生成化合物已被证明在其他肿瘤类型中能与化疗化合物协同作用，基于血管正常化，原发性脑肿瘤也有采用这种联合疗法的趋势。然而，脑中的血管正常化可能导致血脑屏障的恢复，从而影响化疗药物的疗效。在本研究中，我们对这一假设进行了调查。将接种了人胶质母细胞瘤细胞系E98或U87脑内异种移植物的BALB/c裸鼠用不同剂量的凡德他尼（一种血管生成抑制剂）、替莫唑胺（一种DNA烷化剂）或联合用药进行治疗（每组n>8）。凡德他尼选择性地抑制了胶质瘤的血管生成生长方面并恢复了血脑屏障。它对弥漫性浸润生长和存活没有显著影响。此外，凡德他尼可能通过恢复血脑屏障和阻碍化疗药物向肿瘤细胞的化学分布来拮抗替莫唑胺的作用。肿瘤微环境是对抗血管生成治疗反应的一个极其重要的决定因素。特别是在脑中，抗血管生成化合物与化疗联合使用时可能会产生不良反应。因此，在神经肿瘤学中使用此类化合物应重新考虑。
