Huang Jianzhong, Frischer Jason S, New Tamara, Kim Eugene S, Serur Anna, Lee Alice, Kadenhe-Chiwishe Angela, Pollyea Daniel A, Yokoi Akiko, Holash Jocelyn, Yancopoulos George D, Kandel Jessica J, Yamashiro Darrell J
Division of Pediatric Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
Mol Cancer Ther. 2004 Mar;3(3):335-43.
TNP-470 (AGM-1470), an analogue of fumagillin, was one of the first molecules proposed to have antiangiogenic properties. This concept was based on its ability to inhibit both endothelial proliferation in vitro and tumor growth in vivo in a number of xenograft models. Yet, subsequent investigations indicated that the biochemical activities associated with TNP-470 are not selective for endothelial cells. Moreover, recent evidence suggests that this agent inhibits tumor growth in vivo, but without a corresponding decrease in angiogenesis. Therefore, we performed a detailed comparison of TNP-470 to a validated antiangiogenic agent, a VEGF inhibitor termed VEGF-Trap, using a xenograft model of Wilms tumor. Treatment with TNP-470 for 5 weeks significantly suppressed xenograft growth (83%). Surprisingly, this inhibition was not associated with a decrease in angiogenesis, but instead with an increase in tiny neovessels. To determine whether this was a direct effect of TNP-470 on tumor vessels, we examined its effect in a short-term assay using large tumors with established vasculature. In contrast to treatment with VEGF-Trap, which led to rapid vessel regression and tumor hypoxia, tumors exposed to TNP-470 for 1 day displayed increased capillary sprouting, with significantly increased microvessel density, vessel length, and branch points. TNP-470 did not induce tumor hypoxia as demonstrated by minimal pimonidazole staining and VEGF expression. TNP-470 did, however, cause a marked increase in apoptosis of tumor cells. Our results indicate that the antitumor effects of TNP-470 cannot be attributed to prevention of neoangiogenesis, but instead to its direct action on tumor cells.
TNP - 470（AGM - 1470）是烟曲霉素的类似物，是最早被提出具有抗血管生成特性的分子之一。这一概念基于其在多种异种移植模型中抑制体外内皮细胞增殖和体内肿瘤生长的能力。然而，随后的研究表明，与TNP - 470相关的生化活性并非内皮细胞所特有。此外，最近的证据表明，该药物在体内抑制肿瘤生长，但血管生成并未相应减少。因此，我们使用肾母细胞瘤异种移植模型，对TNP - 470与一种经过验证的抗血管生成药物——一种名为VEGF - Trap的VEGF抑制剂进行了详细比较。用TNP - 470治疗5周可显著抑制异种移植瘤生长（83%）。令人惊讶的是，这种抑制与血管生成减少无关，而是与微小新血管的增加有关。为了确定这是否是TNP - 470对肿瘤血管的直接作用，我们在一个使用具有成熟脉管系统的大肿瘤的短期试验中研究了其作用。与VEGF - Trap治疗导致血管迅速消退和肿瘤缺氧相反，暴露于TNP - 470 1天的肿瘤显示毛细血管芽生增加，微血管密度、血管长度和分支点显著增加。如最小的匹莫硝唑染色和VEGF表达所示，TNP - 470未诱导肿瘤缺氧。然而，TNP - 470确实导致肿瘤细胞凋亡显著增加。我们的结果表明，TNP - 470的抗肿瘤作用不能归因于对新生血管生成的预防，而是归因于其对肿瘤细胞的直接作用。
