Explore and development of anti-tumor substances from natural medicinal drugs through the inhibition of tumor-induced angiogenesis and the stimulation of immune functions

本研究从天然药物中分离出抗肿瘤物质作为抑制肿瘤新生血管和刺激免疫功能的靶点。研究结果总结如下：1。从姬松茸中分离出抗血管生成物质A-1和A-2，并将其作为基质添加血管内皮生长因子（VEGF）诱导血管生成的实验体系。A-1被鉴定为焦谷氨酸钠。A-1抑制Lewis肺癌（LLC）小鼠肿瘤生长和肺转移。此外，口服A-1可抑制llc -荷瘤小鼠脾淋巴细胞、CD4+和CD8+ T细胞数量的减少。此外，A-1增加了侵袭肿瘤的CD8+ T和自然杀伤细胞的数量。上述结果提示，A-1（焦谷氨酸钠）的抗转移作用可能与抑制肿瘤生长引起的免疫反应降低和肿瘤诱导的新血管形成有关。从当归根中分离出抗肿瘤物质4-羟基苦参素在本实验中，从当归根中分离出两种黄色物质（I和II）作为抗肿瘤物质，经鉴定，I和II分别为黄原angelol和4-羟基苦参素。我们最近报道了黄原angelol通过抑制肿瘤诱导的血管生成来抑制肿瘤生长和肺转移。然后用LLC-bearing小鼠检测4-羟基苦参素的抗肿瘤和抗肿瘤作用。4-羟基苦参能抑制皮下植入llc小鼠的肿瘤生长，抑制皮下肿瘤手术切除后小鼠的肺转移，延长小鼠存活时间。此外，4-羟基莪术素可抑制肿瘤切除小鼠脾脏淋巴细胞、CD4^+T、CD8^+T和自然杀伤细胞（NK）数量的减少。提示4-羟基苦参素的抗肿瘤和抗转移活性可能受免疫系统调节。新型二十碳五烯酸（eicosapentaenoic acid， EPA）衍生物的分离、结构测定及其抗肿瘤和抗转移作用EPA加速稳定性试验中形成的二十碳五烯酸衍生物通过抑制血管生成和刺激免疫功能抑制肝癌小鼠的肿瘤生长和肺转移。EPA衍生物由新鉴定的EPA乙基二聚体和EPA羟乙基lester，以及已知的EPA和EPA乙基酯的混合物组成。EPA乙基二聚体和EPA羟乙基二聚体均能提高LLC细胞的产氧能力，且EPA乙基二聚体的作用强于EPA乙基二聚体。因此，这些研究结果表明，EPA乙酯二聚体和EPA羟乙酯形成的EPA乙酯可能是抗肿瘤药物的候选化合物，以及EPA乙酯的抗肿瘤作用。少

This study was examined the isolation of antitumor substances from natural medicinal drugs as the targets with the inhibition of tumor-induced neovascularization and the stimulation of immune function. The summary of the research results were described as follows ;1.Isolation of anti-angiogenic substance from Agaricus blazein Murill : Its antitumor and antimetastatic actionsTwo anti-angiogenic substances (A-1 and A-2) were isolated from A.blazei using as assay system of angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor (VEGF). A-1 was identified as sodium pyroglutamate. A-1 inhibited tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. Futhermore, the reduction of the numbers of splenic lymphocytes, CD4+ and CD8+ T cells in LLC-bearing mice was inhibited by the oral administration of A-1. Furthermore, A-1 increased the numbers of CD8+ T and natural killer cells invading the tumors. These results suggest that the antitum … More or and antimetastatic actions of A-1 (sodium pyroglutamate) may be associated with inhibition of the reduction of immune response caused by the tumor growth and tumor-induced neovascularization.2.Isolation of antitumor substance, 4-hydroxyderricin from Angelica keiskei rootsIn the preset study, two yellow substances (I and II) were isolated from Anglica keiskei roots as antitumor substances, and then I and II were identified as xantoangelol and 4-hydroxyderricin. We recently reported that xanthoangelol inhibited tumor growth and metastasis to the lung through the inhibition of tumor-induced angiogenesis. And then, the antitumor and antimetastic actions of 4-hydroxyderricin were examined using LLC-bearing mice. 4-Hydroxyderricin inhibited the tumor growth in subcutaneous LLC-implanted mice and inhibited the lung metastasis and prolonged the survival time in mice after the removal of subcutaneous tumors by surgical operation. In addition, 4-hydroxyderricin inhibited the reduction of numbers of lymphocytes, CD4^+T, CD8^+T and natural killer (NK) cells in the spleen of tumor-removed mice. These results suggest that the antitumor and antimetastatic activities of 4-hydroxyderricin may be modulated by the immune system.3.Isolation and structural determination of novel eicosapentaenoic acid (EPA) derivatives and its antitumor and antimetastatic actionsEPA derivatives formed during accelerated stability testing of EPA, inhibited the tumor growth and metastasis to the lung in LLC-bearing mice through the anti-angiogenesis and the stimulation immune function. EPA derivatives are composed of a mixture of a newly identified EPA ethylester dimer and EPA hydroxyethylester, and known EPA and EPA ethylesters. EPA ethylester dimer and EPA hydroxyethylester increased the O2- production by LLC cells, and the effects of EPA ethylester dimer was stringer than that of EPA ethylester. Therefore, these findings suggest that EPA ethylester dimer and EPA hydroxyethylester formed EPA ethylester may be a candidate compound for antitumor agents as well as the antitumor action of EPA ethylester. Less