Distinct response of experimental neuroblastoma to combination antiangiogenic strategies

Background: The authors have shown previously that experimental neuroblastoma is partially inhibited (48%) by antivascular endothelial growth factor (anti-VEGF) antibody. The topoisomerase-I inhibitor, topotecan, has been shown to have antiangiogenic activity when administered in a low-dose, high-frequency regimen. We hypothesized that combining topotecan with anti-VEGF would suppress neuroblastoma more effectively than either agent alone. Methods: A total of 10(6) neuroblastoma cells were implanted intrarenally in athymic mice. Animals received vehicle, topotecan, anti-VEGF, or topotecan plus anti-VEGF (n = 9, 20, 20, 20, respectively). All control and half the treated mice were killed at 6 weeks. Remaining (rebound) mice were maintained without treatment for 3 more weeks. Patterns of vasculature and apoptosis were determined immunohistochemically. Results: Tumor weights at 6 weeks were reduced significantly in topotecan-only (0.07 g) and combination-treated animals (0.08 g), compared with controls or anti-VEGF-treated mice (1.18 g, 0.53 g; P < .0007, all). At 9 weeks, rebound tumor weights were greatest in anti-VEGF (2.82 g), intermediate in topotecan (1.82 g), and least in combination-treated animals (1.47 g); however, the only significant difference was between anti-VEGF and combination therapy (P = 0.04). All treated tumors were vascularized sparsely in comparison with controls at 6 weeks, but exhibited brisk neoangiogenesis at 9 weeks. Conclusions: Topotecan either with or without anti-VEGF antibody significantly suppresses neuroblastoma xenograft growth in comparison with controls or anti-VEGF antibody alone. Combining topotecan with anti-VEGF antibody significantly inhibited rebound tumor growth in comparison with anti-VEGF antibody alone. Combination therapy may improve durability of antiangiogenic inhibition of neuroblastoma.