Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D
Department of Biochemistry and Biophysics, Hormone Research Institute, University of California, San Francisco, CA 94143-0534, USA.
Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2002-7. doi: 10.1073/pnas.93.5.2002.
Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.
在实体瘤出现之前的多阶段肿瘤发生过程中，血管生成被激活。我们使用转基因小鼠模型，测试了血管生成抑制剂治疗能够在转变为血管生成表型后抑制肿瘤发生进程这一命题。在该模型中，胰岛细胞癌由多灶性、过度增殖性结节发展而来，这些结节显示出人类原位癌的组织学特征。用血管生成抑制剂AGM - 1470（TNP - 470）、抗生素米诺环素和干扰素α/β联合治疗小鼠。治疗方案显著减缓了肿瘤生长，但并未阻止肿瘤形成；肿瘤体积降至对照组的11%，毛细血管密度降至对照组的40%。治疗组和对照组小鼠肿瘤细胞的增殖指数相似，而治疗组肿瘤的凋亡指数增加了一倍。这项研究表明，从头开始的肿瘤进展仅通过抗血管生成疗法就可以受到限制。结果表明，血管生成抑制剂是旨在阻止肿瘤发生离散阶段进展的抗癌策略的有效组成部分，并证明转基因小鼠模型可用于评估候选抗血管生成药物的疗效。
