Effects of cytogenin, a novel microbial product, on embryonic and tumor cell-induced angiogenic responses in vivo.
Effects of cytogenin, a novel microbial product, on embryonic and tumor cell-induced angiogenic responses in vivo.
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发表时间：
1997-05
影响因子：
2
通讯作者：
Tsutomu Oikawa;M. Sasaki;M. Inose;Mariko Shimamura;Hiroshi Kuboki;Satoshi Hirano;Hiroyuki Kumagai;Masaaki Ishizuka;T. Takeuchi
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文献类型：
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作者：
Tsutomu Oikawa;M. Sasaki;M. Inose;Mariko Shimamura;Hiroshi Kuboki;Satoshi Hirano;Hiroyuki Kumagai;Masaaki Ishizuka;T. Takeuchi
细胞生成素（8-羟基-3-羟甲基-6-甲氧基异香豆素）是一种新的微生物制剂，口服具有抗肿瘤和抗类风湿关节炎的作用，但其作用机制尚不清楚。肿瘤和类风湿性关节炎都被称为血管生成依赖性疾病。本研究的目的是探讨细胞生成素对生理和病理性血管生成的影响，使用生长鸡胚绒毛尿囊膜和小鼠背气囊测定系统，分别。当局部置于绒毛尿囊膜表面时，剂量高达100微克/卵的微生物产品对胚胎血管生成没有显著影响，表明其对生理（或正常）血管生成反应没有影响。相比之下，全身施用细胞生成素（100 mg/kg p.o.，在小鼠背气囊实验系统中，连续5天）显著抑制恶性肿瘤细胞（S-180）诱导的血管生成，这是病理性新生血管的一种。在小鼠中的药代动力学研究显示，在单次口服100 mg/kg剂量的化合物后，血浆中细胞生成素的最大浓度为32 μ M。体外培养血管内皮细胞的实验表明，在药代动力学研究确定的浓度下，细胞生成素对纤溶酶原激活物分泌、管形成和内皮细胞增殖的影响很小。这些结果表明，cytogenin是一种新的口服抗血管生成剂，其抗血管生成作用的机制有助于其抑制肿瘤生长和类风湿性关节炎，我们以前发现，它可以开发为一个潜在的治疗剂，癌症，类风湿性关节炎和其他血管生成依赖性疾病，如糖尿病视网膜病变。
Cytogenin (8-hydroxy-3-hydroxymethyl-6-methoxyisocoumarin) is a new microbial product with antitumor and antirheumatoid arthritis effects in vivo when administered orally, although its mechanism(s) of action is not known well. Both neoplasia and rheumatoid arthritis are referred to as angiogenesis-dependent diseases. The aim of the present study was to investigate the effects of cytogenin on both physiological and pathological angiogenesis, using the growing chick embryo chorioallantoic membrane and mouse dorsal air sac assay systems, respectively. The microbial product at doses up to 100 micrograms/egg did not significantly affect embryonic angiogenesis when topically placed on the surface of the chorioallantoic membrane, suggesting that it has no effect on the physiological (or normal) angiogenic response. By contrast, systemic administration of cytogenin (100 mg/kg p.o., for 5 consecutive days) significantly suppressed angiogenesis induced by malignant tumor cells (S-180), one of pathological neovascularization, in a mouse dorsal air sac assay system. Pharmacokinetic studies in mice revealed that the maximal concentration of cytogenin in plasma after a single 100 mg/kg oral dose of the compound was 32 microM. In vitro experiments involving cultured vascular endothelial cells showed that cytogenin at concentrations determined by pharmacokinetic study, had little effect on plasminogen activator secretion, tube formation and the proliferation of endothelial cells. These results suggest that cytogenin is a novel oral antiangiogenic agent, that the mechanism of its antiangiogenic action contributes to its suppressive effects on both tumor growth and rheumatoid arthritis that we previously found, and that it could be developed as a potential therapeutic agent for cancer, rheumatoid arthritis and other angiogenesis-dependent disorders such as diabetic retinopathy.