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Research Articles: Therapeutics, Targets, and Development

Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization

Departments of ¹ Pathology and ² Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Requests for reprints: William P.J. Leenders, Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-243614289; Fax: 31-243668750. E-mail: w.leenders{at}pathol.umcn.nl

Abstract

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. [Mol Cancer Ther 2008;7(1):71–8]

Grant support: Hersenstichting Nederland grant 12F04.(02).2 (W.P.J. Leenders) and Dutch Cancer Society grant 2003-2975 (A. Claes and P. Wesseling).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Unpublished results.

⁴ Int. J. Cancer., in press.

Received 8/ 9/07; revised 9/28/07; accepted 11/12/07.