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Simi larly, sunitinib induced blockade of VEGFR and PDGFR has been reported to improve vascular function in human glioma xenografts, whereas the current study shows that sunitinib treatment does not improve vascular function in human melanoma xenografts. Con sequently, whether antiangiogenic overnight delivery treatment improves vascular function, does not reflect whether the antian giogenic agent blocks PDGFR in addition to VEGFR, but more likely reflects differences in tumor models. In addition to improve tumor blood supply and oxygenation, antiangiogenic agents have also been reported to reduce vessel permeability and lower tumor IFP in preclinical models. These effects have collectively been referred to as vascular normalization.

Moreover, increased hypoxic fractions, reduced vessel permeability, and lowered tumor IFP have been observed simultaneously after antiangio genic treatment. This observation suggests that improved tumor oxygenation, normalized vessel per meability, and normalized tumor IFP may not neces sarily occur in parallel temporal windows . Consequently, although sunitinib treatment did not improve blood supply and oxygenation in A 07 GFP and R 18 GFP tumors, we cannot rule out the possibility that sunitinib treatment may normalize vessel permeability and tumor IFP in these tumor models. Sunitinib has been shown to prolong progression free and overall survival in patients with imatinib refractory GIST and metastatic RCC in clinical phase III trials, and has been approved by the US Food and Drug Adminis tration for these indications.

However, the tumors eventually become unresponsive to sunitinib, and the benefits in progression free and overall survival are measured in months. Treatment regimes that com bine sunitinib with ionizing radiation, different che motherapeutic agents, or other antiangiogenic agents may enhance and prolong the effects of sunitinib, and clinical studies that evaluate such combinations are on going. The current study and previously reported preclinical studies suggest that antiangiogenic treatment improves vascular function and tumor oxygenation in some cli nical tumors, and induces hypoxia in others. Neoadju vant antiangiogenic therapy may enhance the effect of ionizing radiation or chemotherapy in clinical tumors where antiangiogenic treatment improves vascular function.

The feasibility of this strategy has been demon strated in preclinical studies where maximal antitumor ef fect of ionizing radiation was achieved when tumors were irradiated within the time period when tumor oxygenation was improved by antiangiogenic treatment. On the other hand, in clinical tumors where antiangiogenic treat ment induces hypoxia, neoadjuvant antiangiogenic therapy is expected to reduce the effect of ionizing radiation or chemotherapy.