gms | German Medical Science

Prominent angiogenesis is a hallmark of high grade gliomas, therefore new treatment approaches focus on targeting their vasculature. However, first experiences with anti-angiogenic drugs display shortcomings, among others a phenotypic switch to increased migratory potential of glioma cells. This might be attributed to the latency between application and final effects of anti-angiogenic drugs enabling tumors to adapt to therapy-induced changes. In contrast, vascular disrupting agents (VDA) exert their impact on established tumor blood vessels within minutes leading to a vacular collapse followed by extensive tumor necrosis. The small molecule ASA-404 is a VDA inducing apoptosis in tumor endothelial cells. Since there is poor data concerning ASA-404 effects on malignant gliomas, our aim was to investigate its applicability in a brain tumor model. Human glioma (U87MG, U251MG, LN-308 and LN-229), colon carcinoma (HT29) and mouse brain endothelial cells (bEnd.3) were exposed to increasing concentrations of ASA-404 in vitro to determine the sensitivity of tumor and endothelial cells. For in vivo studies, glioma cells were injected subcutaneously or intracranially in nude mice. Mice were treated with intraperitoneal injections of ASA-404 (25 mg/kg) or with PBS. 24 h after treatment animals were sacrificed and tumors removed for histological analysis. In vitro, we found cytotoxic effects of ASA-404 above 0.01 mg/ml with slightly increased sensitivity for bEnd.3. The subcutaneously ASA-404-treated tumors displayed gross haemorrhages already few hours after treatment. Histological analysis showed large necrotic areas encompassing over 70% of the whole tumor. At the border between vital and necrotic tumor, extensive micro-bleedings were found. In addition, in the remaining vital parts increased apoptosis and reduced proliferation was observed. Most interestingly, intracranial tumors did not reveal the same responses to ASA-404, however tumors showing connection between intra- and extracerebral parts only displayed responses to ASA-404 in the extracerebral, subcutaneous part. In conclusion, our results indicate that ASA-404 is an efficient drug selectively targeting tumor vessels in extracerebral tumors. These results might probably be due to a different intratumoral vascularization in the brain.