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In vitro and in vivo endochondral bone formation models allow identification of anti-angiogenic compounds

AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 157-163页

作者： van der Pluijm, G Deckers, M Sijmons, B de Groot, H Bird, J Wills, R Papapoulos, S Baxter, A Löwik, C Leiden Univ Med Ctr Dept Endocrinol NL-2333 ZA Leiden Netherlands CellTech R&D Ltd Cambridge England

A major obstacle in the study of angiogenesis and the testing of new agents with anti-angiogenic potential has been the lack of experimental models with predictive in vivo value. We describe here the combined use of in vitro and in vivo angiogenesis models that are based on endochondral bone development This approach led to the identification of a new inhibitor of matrix metalloprotease (MMP) activity that inhibits neovascularization in vitro and in vivo while osteoclast invasion, which occurs simultaneously during bone development, remained unaffected. In contrast, the broad-spectrum MMP-inhibitor marimastat inhibited both in vitro angiogenesis and osteoclastogenesis dose-dependently but displayed severe toxic side effects in vivo. The combined use of these experimental models may, therefore, facilitate the discovery of mechanisms underlying angiogenesis and lead to identification of new pharmacological compounds with clinical efficacy and appropriate selectivity in the treatment of angiogenesis-dependent disorders like arthritis and cancer.

关键词：血管生成抑制剂/代谢骨发育/生理学骨质吸收/代谢酶抑制剂/代谢羟肟酸类/代谢基质金属蛋白酶类/代谢跖骨/细胞学跖骨/代谢模型生物学新生血管化生理性破骨细胞/细胞学破骨细胞/代谢动物人类小鼠

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The antiangiogenic agent TNP-470 requires p53 and p21^CIP/WAF for endothelial cell growth arrest

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第23期97卷 12782-12787页

作者： Yeh, JRJ Mohan, R Crews, CM Yale Univ Dept Mol Cellular & Dev Biol New Haven CT 06520 USA Yale Univ Dept Pharmacol New Haven CT 06520 USA

Targeting the endothelial cell cycle as an antiangiogenic strategy has been difficult given the ubiquitous expression of critical cell cycle regulators. Here, we show that the antiangiogenic drug TNP-470 displays striking cell-type specificity insofar as it induces the expression of p21(CIP/WAF), a cyclin-dependent kinase inhibitor. in endothelial cells but not in embryonic or adult fibroblasts. Moreover, primary endothelial cells isolated from p53(-/-) and p21(CIP/WAF-/-) mice are resistant to the cytostatic activity of TNP-470. We also demonstrate that p21(CIP/WAF-/-) mice are resistant to the antiangiogenic activity of TNP-470 in the basic fibroblast growth factor corneal micropocket angiogenesis assay. We conclude that TNP-470 induces p53 activation through a unique mechanism in endothelial cells leading to p21(CIP/WAF) expression and subsequent growth arrest.

关键词：血管生成抑制剂/代谢血管生成抑制剂/药理学细胞培养的角膜新生血管化周期素依赖激酶抑制剂p21 细胞周期蛋白类/遗传学细胞周期蛋白类/代谢环己烷类小鼠基因敲除核蛋白质类原癌基因蛋白质类/代谢原癌基因蛋白质c-mdm2 倍半萜类/代谢倍半萜类/药理学肿瘤抑制蛋白质p53/遗传学肿瘤抑制蛋白质p53/代谢成年人动物人类小鼠

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Angiogenesis inhibition by transdominant mutant Ets-1

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期184卷 255-262页

作者： Nakano, T Abe, M Tanaka, K Shineha, R Satomi, S Sato, Y Tohoku Univ Inst Dev Aging & Canc Dept Vasc Biol Aoba Ku Sendai Miyagi 9808575 Japan Tohoku Univ Sch Med Dept Surg 2 Sendai Miyagi 9808575 Japan

The expression of transcription factor Ets-1 is induced in endothelial cells (ECs) by angiogenic factor;and in turn Ets-1 converts ECs to angiogenic invasive phenotype. In order to control angiogenesis, we constructed a transdominant mutant Ets-1 (TMEts-1) which acts as a dominant negative molecule. This molecule inhibited the DNA binding and the transactivation activity of the wild-type Ets-1. Stable transfection of murine Endothelial cell line MSS31 cells with the TMets-1 gene impaired angiogenic activities including proliferation, migration, invasion, and tube formation in type-1 collagen gel. Finally, we incorporated the TMets-1 gene into a non-proliferative adenovirus vector, designated as AdTMets-1. AdTMets-1 significantly inhibited angiogenesis in the Matrigel plugs injected into the subcutaneous tissue of C57BL mice. These results indicate that TMets-1 would be a tool for angiogenic inhibition. J. Cell. Physiol. 184:255-262, 2000. (C) 2000 Wiley-Liss, Inc.

关键词： 3T3细胞腺病毒科/遗传学腺病毒科/代谢血管生成抑制剂/代谢内皮/代谢遗传载体/遗传学遗传载体/代谢突变新生血管化病理性/代谢原癌基因蛋白质c-ets-1 原癌基因蛋白质类/遗传学原癌基因蛋白质类/代谢原癌基因蛋白质c-ets 转录因子/遗传学转录因子/代谢转染/遗传学肿瘤细胞培养的动物小鼠

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Wielding more power over angiogenesis

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MOLECULAR MEDICINE TODAY 2000年第4期6卷 138-139页

作者： Habeck, M

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Angiogenesis and surgery: from mice to man

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EUROPEAN JOURNAL OF SURGERY 2000年第6期166卷 435-446页

作者： Drixler, TA Voest, EE van Vroonhoven, TJMV Rinkes, IHMB Univ Utrecht Med Ctr Dept Surg NL-3508 GA Utrecht Netherlands Univ Utrecht Med Ctr Dept Med Oncol NL-3508 GA Utrecht Netherlands

Describes state of knowledge on angiogenesis based on experimental data important to surgeons. Discussion on tumor-associated angiogenesis; Review on important factors involved in angiogenesis; Presentation of clinica... 详细信息

关键词：血管生成抑制剂/代谢血管生成抑制剂/治疗应用血管抑制素类抗肿瘤药/代谢毛细血管通透性胶原/生理学内皮抑素类预测生长物质/代谢金属内肽酶类/代谢肿瘤/药物疗法新生血管化病理性/病理生理学肽碎片/代谢肽碎片/生理学纤维蛋白溶酶原/代谢蛋白酶抑制药/代谢凝血酶敏感蛋白类/生理学伤口愈合/生理学动物人类小鼠

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Template-constrained cyclic peptide analogues of somatostatin: Subtype-selective binding to somatostatin receptors and antiangiogenic activity

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BIOORGANIC & MEDICINAL CHEMISTRY 2000年第9期8卷 2229-2241页

作者： Suich, DJ Mousa, SA Singh, G Liapakis, G Reisine, T DeGrado, WF Univ Penn Dept Biochem & Biophys Philadelphia PA 19104 USA Dupont Merck Pharmaceut Co Wilmington DE 19880 USA Univ Penn Dept Pharmacol Philadelphia PA 19104 USA

beta-Turns are a common secondary structure motif found in proteins that play a role in protein folding and stability and participate in molecular recognition interactions. Somatostatin, a peptide hormone possessing a variety of therapeutically-interesting biological acitivities, contains a beta-turn in its bioactive conformation. The beta-turn and biological activities of somatostatin have been succesfully mimicked in cyclic hexapeptide analogues. Two novel, structured, non-peptidic molecules were developed that are capable of holding the bioactive tetrapeptide sequence of somatostatin analogues in a beta-turn conformation, as measured by somatostatin receptor (SSTR) binding. Template-constrained cyclic peptides in which the ends of the -Tyr-D-Trp-Lys-Val-tetrapeptide were linked by scaffolds based on either an N,N'-dimethyl-N,N'-diphenylurea or a substituted biphenyl system (DJS631 and DJS811, respectively), bound selectively to mouse SSTR2B and rat and human SSTR5 with affinities as high as 1 nM. DJS811, at a dose of 3 mg/kg/day, was shown in a mouse Matrigel model to inhibit angiogenesis to a level of 79%. The development of structured turn scaffolds allows beta-turn sequences to be contained in the context of a compact structure, with less peptidic nature and potentially greater bioavailability than cyclic hexapeptides. These systems can be used to study the determinants of beta-turn formation, as well as to probe the importance of turn sequences occurring in molecular recognition interactions. The antiangiogenic activity of DJS811 suggests that it may have antitumor activity as well. In addition, because SSTR2 is overexpressed on many types of tumors, DJS631 and DJS811 may be useful in the development of agents for tumor imaging or the radiotherapy of cancer. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：血管生成抑制剂/代谢半数抑制浓度模型动物分子模拟新生血管化生理性/药物作用肽类环/化学合成肽类环/代谢肽类环/药理学苯脲化合物/化学合成苯脲化合物/代谢苯脲化合物/药理学蛋白质结合蛋白质结构二级受体生长抑素/代谢生长抑素/类似物和衍生物构效关系热力学动物人类小鼠大鼠

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Thrombospondin-2: A potent endogenous inhibitor of tumor growth and angiogenesis

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第26期96卷 14888-14893页

作者： Streit, M Riccardi, L Velasco, P Brown, LF Hawighorst, T Bornstein, P Detmar, M Massachusetts Gen Hosp Cutaneous Biol Res Ctr Charlestown MA 02129 USA Massachusetts Gen Hosp Dept Dermatol Charlestown MA 02129 USA Harvard Univ Sch Med Charlestown MA 02129 USA Harvard Univ Sch Med Boston MA 02215 USA Beth Israel Deaconess Med Ctr Dept Pathol Boston MA 02215 USA Univ Washington Dept Biochem Seattle WA 98195 USA

Recent evidence suggests a potential role for thrombospondin-2 (TSP-2), a matricellular glycoprotein, in the regulation of primary angiogenesis. To directly examine the biological effect of TSP-2 expression on tumor growth and angiogenesis, human A431 squamous cell carcinoma cells, which do not express TSP-2, were stably transfected with a murine TSP-2 expression vector or with vector alone. A431 cells expressing TSP-2 did not show an altered growth rate, colony-forming ability, or susceptibility to induction of apoptosis in vitro. However, injection of TSP-2-transfected clones into the dermis of nude mice resulted in pronounced inhibition of tumor growth that was significantly stronger than the inhibition observed in A431 clones stably transfected with a thrombospondin-1 (TSP-1) expression vector, and combined overexpression of TSP-1 and TSP-2 completely prevented tumor formation. Extensive areas of necrosis were observed in TSP-2-expressing tumors, and both the density and the size of tumor vessels were significantly reduced, although tumor cell expression of the major tumor angiogenesis factor, vascular endothelial growth factor, was maintained at high levels. These findings establish TSP-2 as a potent endogenous inhibitor of tumor growth and angiogenesis.

关键词：血管生成抑制剂/代谢抗肿瘤药/代谢癌鳞状细胞/预防和控制小鼠近交BALBC 小鼠裸肿瘤实验性/预防和控制新生血管化病理性/预防和控制重组蛋白质类/代谢凝血酶敏感蛋白类/遗传学凝血酶敏感蛋白类/代谢肿瘤细胞培养的动物人类小鼠

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