Angiogenesis Inhibitors

Tumor vascularity is highly correlated with outcome. The role for anti-angiogenic, and in vivo angiogenic, activity of neuroblastoma correlates with MYCN oncogene overexpression (Ribatti et al. 2002). Consequently, anti-angiogenic agents have been extensively investigated in neuroblastoma xenograft models. Results have been variable. In the study by Katzenstein et al. (1999) initiating therapy with TNP-470 before tumors were clinically evident resulted in 53% of mice being tumor free at 12 weeks. When tumors were staged (<400 mm3) drug treatment significantly retarded growth of NBL-W-N neuroblastomas, whereas treatment had no effect when tumors were larger (>400 mm3) at the start of treatment. Similar results were obtained with CHP-134 xenografts (Shusterman et al. 2000,2001). Other studies (Kim et al. 2002) demonstrated that blockade of VEGF using anti-human VEGF (165) RNA-based fluoropyrimi-dine aptamer, a monoclonal anti-human VEGF antibody and a VEGFR-1 and VEGFR-2 decoy receptor (VEGF-Trap), inhibited growth NGP-GFP neuroblastomas. Of these the VEGF-Trap approach gave the greatest tumor inhibition; however, in the presence of prolonged inhibition of VEGF function tumors persisted in cooption of blood vessels. This may explain why experimental neuroblastoma may be less sensitive to inhibiting VEGF than another model of Wilms' tumor. Recombinant human and murine endostatin has been evaluated against TNB9 and SKNAS neu-roblastoma models, respectively (Jouanneau et al. 2001; Kuroiwa et al. 2001). Both studies initiated therapy when tumors were relatively small, but neither study showed a significant inhibition of tumor growth. Similarly, the VEGFR-2 receptor inhibitor SU6668 demonstrated little activity against several neuroblastoma xenografts (Table 17.2). In contrast, another VEGFR-2 inhibitor SU5416 did inhibit growth of SH-SY5Y tumors by 65 % (Backman et al. 2002). A novel approach to controlling angiogenesis through inhibition of hypoxia-inducible factor 1a (HIF-1a) has been tested in various xenograft models including neuroblastoma (Yeo et al. 2003). YC-1, an inhibitor of HIF-1a significantly retarded growth of SK-N-MC PNET xenografts and decreased vascu-larization. These diverse results reported with different anti-angiogenic agents raises the question of how best to evaluate anti-angiogenic agents in mice; indeed, what constitutes the best model systems? Should orthotopic models be prioritized for these studies, or should established tumors be de-bulked by chemotherapy prior to starting the antiangiogenic treatment? These "secondary" screening models would more readily mimic a clinical situation; however, one still has a hybrid model in which it is murine endothelial elements that are targeted in a human tumor. A more extensive evaluation of anti-angiogenic therapies in a panel of subcutaneous or orthotopic neuroblastoma models is required to address these issues.

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