TY - JOUR
T1 - In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP-II
AU - Schwarz, Roderich E.
AU - Schwarz, Margaret A.
N1 - Funding Information:
The authors acknowledge the technical assistance of Fang R. Zhang. Some experiments were performed at in the Division of Pediatric Critical Care Medicine, Children’s Hospital of Los Angeles, California (P.I.: Margaret A. Schwarz). The presented work was supported in part by Grants HL-60061 and HL-03981 from the National Institutes of Health.
PY - 2004/7
Y1 - 2004/7
N2 - Background Continued growth of solid tumors beyond a critical diameter is thought to require active angiogenic mechanisms, the inhibition of which carries therapeutic potential. We tested this strategy in an in vivo model of local tumor progression utilizing an agent with previously identified direct antiendothelial properties. Materials and methods Nonmetastatic C6 glioma cells (106 per animal) were injected subcutaneously into the flank of nude mice with 6 to 8 animals per treatment group. Nodules at the injection site were measured at day 3 and every fourth day thereafter until day 15. Endothelial-monocyte-activating polypeptide II (EMAP-II), a substance known to induce endothelial cell apoptosis, was injected intraperitoneally daily from day 3 to day 15 at doses of 8 μg/kg (low dose) and 80 μg/kg (high dose). Tumor growth kinetics, histologic parameters, and tissue expression of VEGF were studied. Results Tumor growth was significantly decreased in the EMAP-II-treated animals. Median tumor volume (in mm3) at day 15 was 2311 (Control), 727 (low dose), and 454 (high dose, P = 0.003). Median tumor weight (g) measured 1.8 (Control, 0.95 low dose), and 0.9 (high dose, P = 0.06). Median 12-day specific tumor growth rate (in mm3/day) per group was 191, 60, and 36 (P = 0.003). Decreased tumor growth after EMAP-II treatment correlated with significantly reduced microvessel counts, higher vascular thrombosis rate, and reduced tumor cell proliferation indices within the neoplastic tissue. Tumor levels, but not serum levels, of VEGF were significantly reduced after EMAP-II treatment. At the doses administered, there was no obvious systemic toxicity. EMAP-II had no direct cytotoxic or antiproliferative effects on tumor cells in vitro. Conclusions Daily administration of the antiendothelial agent EMAP-II led to a significant retardation of tumor growth, but no complete cancer abrogation. The findings support the hypothesis of an in vivo therapeutic benefit to antiangiogenic therapy with an agent that displays specific toxicity in vitro against endothelial cells. The mechanism of action remains unclear, but likely involves vascular thrombosis and leads to decreased VEGF expression.
AB - Background Continued growth of solid tumors beyond a critical diameter is thought to require active angiogenic mechanisms, the inhibition of which carries therapeutic potential. We tested this strategy in an in vivo model of local tumor progression utilizing an agent with previously identified direct antiendothelial properties. Materials and methods Nonmetastatic C6 glioma cells (106 per animal) were injected subcutaneously into the flank of nude mice with 6 to 8 animals per treatment group. Nodules at the injection site were measured at day 3 and every fourth day thereafter until day 15. Endothelial-monocyte-activating polypeptide II (EMAP-II), a substance known to induce endothelial cell apoptosis, was injected intraperitoneally daily from day 3 to day 15 at doses of 8 μg/kg (low dose) and 80 μg/kg (high dose). Tumor growth kinetics, histologic parameters, and tissue expression of VEGF were studied. Results Tumor growth was significantly decreased in the EMAP-II-treated animals. Median tumor volume (in mm3) at day 15 was 2311 (Control), 727 (low dose), and 454 (high dose, P = 0.003). Median tumor weight (g) measured 1.8 (Control, 0.95 low dose), and 0.9 (high dose, P = 0.06). Median 12-day specific tumor growth rate (in mm3/day) per group was 191, 60, and 36 (P = 0.003). Decreased tumor growth after EMAP-II treatment correlated with significantly reduced microvessel counts, higher vascular thrombosis rate, and reduced tumor cell proliferation indices within the neoplastic tissue. Tumor levels, but not serum levels, of VEGF were significantly reduced after EMAP-II treatment. At the doses administered, there was no obvious systemic toxicity. EMAP-II had no direct cytotoxic or antiproliferative effects on tumor cells in vitro. Conclusions Daily administration of the antiendothelial agent EMAP-II led to a significant retardation of tumor growth, but no complete cancer abrogation. The findings support the hypothesis of an in vivo therapeutic benefit to antiangiogenic therapy with an agent that displays specific toxicity in vitro against endothelial cells. The mechanism of action remains unclear, but likely involves vascular thrombosis and leads to decreased VEGF expression.
KW - angiogenesis
KW - endothelial cell toxicity
KW - endothelial-monocyte activating polypeptide II
KW - tumor cell proliferation
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U2 - 10.1016/j.jss.2003.10.005
DO - 10.1016/j.jss.2003.10.005
M3 - Article
C2 - 15172191
AN - SCOPUS:2542467676
SN - 0022-4804
VL - 120
SP - 64
EP - 72
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -