Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy

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Abstract
Current clinical protocols favor a combination of antiangiogenic/antivascular compounds with classical chemotherapy. However, it remains unclear to what extent an antiangiogenic/antivascular therapy influences the delivery of chemotherapy. Therefore, the aim of the present study was to characterize the effects of the antiangiogenic tyrosine kinase inhibitor sunitinib on tumor microhemodynamics and delivery of chemotherapy. SF126 tumor cells were implanted subcutaneously into nude mice and were analyzed repeatedly by intravital microscopy. Treatment with sunitinib was initiated 7 days after implantation. To assess the effects of sunitinib on tumor vasculature and hemodynamics, we analyzed total and functional vessel densities, microvascular diameter, and microvascular blood flow rate. To study the delivery of chemotherapy, autofluorescent doxorubicin was systemically administered and its vascular delivery to the tumor tissue was quantified. Histological analysis included endothelial cell proliferation, pericyte coverage of tumor vessels, and tumor cell proliferation. Sunitinib significantly suppressed tumor growth by both antivascular and antiangiogenic effects. However, a number of tumor vessels escaped antiangiogenic therapy. Interestingly, in these surviving blood vessels sunitinib treatment resulted in an increased microvascular blood flow rate resulting in an improved delivery of chemotherapy via these blood vessels. Besides its potent antiangiogenic and antivascular efficacy, sunitinib treatment results in improved microhemodynamics and blood flow in tumor blood vessels that escape therapy leading to an improved vascular delivery of chemotherapy. These results provide the basis for a potential chemosensitizing effect of sunitinib.