Figure 1. VEGF₁₆₅ conditions tumors for systemic Reo therapy.

(A) Mice bearing B16 tumors established subcutaneously 7 days previously in C57BL/6 mice (5/group) were treated with a single injection per day for 1, 3, or 5 consecutive days of VEGF₁₆₅ (1 μg/injection) (VEGF ×1, ×3, or ×5); 5 daily injections of PBS (PBS ×5); 3 daily injections of PBS followed 24 hours later by a single i.v. injection of Reo (5 × 10⁸ TCID₅₀) (PBS ×3 + Reo); or 3 daily injections of VEGF₁₆₅ followed 24 hours later by a single i.v. injection of Reo (VEGF × 3+Reo). Survival (tumor reaching 1.0 cm in diameter) was followed over time. (B) C57BL/6 mice bearing B16 tumors established 7 days previously in C57BL/6 mice (7–8/group) were treated (days 1–3) with a single injection per day for 3 consecutive days of VEGF₁₆₅ or PBS, followed 24 hours later (days 4, 5) by a single i.v. injection per day for 2 consecutive days of Reo or PBS. This regimen was then repeated (days 8–12 and 15–19) twice in surviving mice. Survival (tumor reaching 1.0 cm in diameter) was followed over time. (C and D) Subcutaneous B16 tumors were examined histologically after being excised 24 hours following a single i.v. injection of Reo administered 24 hours after a single injection per day for 3 consecutive days of either (C) VEGF₁₆₅ or (D) PBS. (E–G) Subcutaneous B16 tumors were examined histologically after being excised 72 hours following 2 daily i.v. injections of Reo administered 24 hours after a single injection per day for 3 consecutive days of either (E) PBS or (F and G) VEGF₁₆₅. Intratumoral hemorrhage/necrosis is shown in F. Perivascular immune infiltrates (thick red arrow) and indistinct tortuous blood vessels (thin red arrow) are shown in G. Original magnification, ×20.