Customizing antiangiogenesis therapy toward vessel normalization results in a long-term glioma growth control

Antiangiogenesis is traditionally targeted to reach the regression of tumor vasculature. Alternatively, antiangiogenesis can be targeted to reach vessel normalization. This needs a careful administration of antivascular agents by tailoring the treatment regimen according to the tumor type and growth behavior. In this work, we investigated whether long-term vessel normalization could be maintained by carefully tailoring the administration of antivascular agents to the occurrence of their therapeutic window toward vessel normalization at a certain stage of tumor progression. We also investigated whether tailored antiangiogenesis therapy results in therapeutic benefit. In an initial set of experiments, we studied the changes in glioma vasculature in the U87 glioma model in nude mice during the various phases of neoplastic development, specifically looking for those that characterize glioma vasculature at different stages of its progression. Secondly, we investigated the efficacy of the administration of known inhibitors of angiogenesis on gliomas at early and late phases of developments, determining foreach inhibitor its therapeutic window toward vessel normalization when administered at a certain stage of tumor progression. Furthermore, we designed tailored schemes of treatment in which the inhibitors were sequentially administered alone or in combination according to their therapeutic windows established at a certain stage of tumor progression. Our findings indicate that by the strategy of carefully tailoring the administration of antiangiogenic agents, it is possible to maintain a long-term status of vessel architecture normalization, and that this results in long-term tumor growth control.