In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP-II.
In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP-II.
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DOI：
10.1016/j.jss.2003.10.005
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发表时间：
2004-07
期刊：
影响因子：
--
通讯作者：
R. Schwarz;M. Schwarz
中科院分区：
文献类型：
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作者：
R. Schwarz;M. Schwarz
研究背景实体瘤的持续生长超过临界直径被认为需要积极的血管生成机制，抑制血管生成机制具有治疗潜力。我们测试了这一战略在体内模型中的局部肿瘤进展，利用先前确定的直接antiendothelial properties.MATERIALS AND METHODSSNonmetastatic C6胶质瘤细胞（106每只动物）皮下注射到裸鼠的侧腹，6至8只动物，每个治疗组。在第3天测量注射部位的结节，此后每4天测量一次，直至第15天。从第3天至第15天，每天腹腔注射8 μg/kg（低剂量）和80 μg/kg（高剂量）的内皮单核细胞激活多肽II（EMAP-II），一种已知可诱导内皮细胞凋亡的物质。研究了肿瘤生长动力学、组织学参数和VEGF的组织表达。EMAP-II治疗的动物肿瘤生长显著减少。第15天的中位肿瘤体积（mm 3）为2311（对照）、727（低剂量）和454（高剂量，P = 0.003）。测量的中位肿瘤重量（g）为1.8（对照，0.95低剂量）和0.9（高剂量，P = 0.06）。每组的中位12天特异性肿瘤生长率（mm 3/天）分别为191、60和36（P = 0.003）。EMAP-II治疗后肿瘤生长减少与肿瘤组织内微血管计数显著减少、血管血栓形成率较高和肿瘤细胞增殖指数降低相关。EMAP-II治疗后，VEGF的肿瘤水平而非血清水平显著降低。在给药剂量下，没有明显的全身毒性。EMAP-II没有直接的细胞毒性或抗增殖作用对肿瘤细胞在vitro.CONCLUSIONSDaily管理的抗内皮剂EMAP-II导致肿瘤生长的显着阻滞，但没有完全消除癌症。研究结果支持了一种在体外对内皮细胞显示特异性毒性的药物进行抗血管生成治疗的体内治疗益处的假设。其作用机制尚不清楚，但可能涉及血管血栓形成并导致VEGF表达降低。
BACKGROUNDContinued 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 METHODSNonmetastatic C6glioma cells (106per 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.RESULTSTumor 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.CONCLUSIONSDaily 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.