Effect of various treatment strategies on tumor growth. (A) Effect of different antiangiogenic strategies on tumor growth. Those therapies that target both the local and systemic pathways, such as anti-VEGF Ab and continuous low-dose chemotherapy combined with anti-VEGFR-2 Ab, are most effective at delaying tumor growth. (B) Relative efficacy of the different antiangiogenic therapies as measured by growth delay. The model predicts a growth delay of 30% or 10.9 d for therapies targeting EC migration, 46% or 21.6 d for therapies targeting VEGF signaling, 55% or 31.2 d for antiangiogenic scheduling of chemotherapy, 61% or 38.7 d for those targeting VEGF, and 64% or 43.9 d for combined continuous low-dose chemotherapy and anti-VEGFR-2 Ab. Therapies on the left target primarily either the local or systemic contribution and increasingly target both contributions more effectively moving to the right. (C) Comparison of vascular density and angiogenic activity during anti-VEGF Ab therapy with the case of no therapy. Normalization of angiogenic activity (α → 0) decreases the vascular density closer to that in normal tissue and greatly delays tumor growth by targeting both the local and systemic pathways. The model predicts a marked reduction in tumor vascular volume during anti-VEGF Ab therapy compared with the case of no therapy (inset). (D) Effect of different chemotherapeutic dosing strategies on tumor growth. The maximum tolerated dose strategy exerts a primarily antitumor effect resulting in a growth delay of 4.9 d. Antiangiogenic scheduling of chemotherapy results in more effective tumor suppression with a growth delay of 55% or 31.2 d. The circulating levels of EPCs predicted during antiangiogenic scheduling of chemotherapy are markedly reduced relative to the case of no treatment (inset). For the case of antiangiogenic scheduling of chemotherapy, doses were administered every6das indicated by the arrows.