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

本研究以天然药物中抗肿瘤物质的分离为靶点，以抑制肿瘤新生血管和刺激免疫功能为研究对象。主要研究结果如下：1.姬松茸抗血管生成物质的分离及其抗肿瘤和抗肿瘤活性利用Matrigel和血管内皮生长因子(VEGF)诱导血管生成的实验体系，从姬松茸中分离得到两个抗血管生成物质(A-1和A-2)。A-1经鉴定为焦谷氨酸钠。A-1可抑制Lewis肺癌(LLC)荷瘤小鼠的肿瘤生长和肺转移。此外，A-1还能抑制荷瘤小鼠脾淋巴细胞、CD_4~+、CD_8~+T细胞的减少。此外，A-1还可增加CD8+T细胞和自然杀伤细胞对肿瘤的侵袭。这些结果表明，抗癌…A-1(焦谷氨酸钠)的抗肿瘤作用可能与抑制肿瘤生长和肿瘤新生血管所引起的免疫反应的降低有关。2.当归抗肿瘤物质4-羟基皮肤素的分离在本实验中，从当归根中分离出两种黄色物质(I和II)作为抗肿瘤活性物质，分别鉴定为黄原醇和4-羟基皮肤素。我们最近报道，黄烷醇通过抑制肿瘤诱导的血管生成来抑制肿瘤的生长和肺转移。然后，用LLC荷瘤小鼠检测了4-羟基地黄毒素的抗肿瘤和抗肿瘤作用。4-羟基皮肤素可抑制皮下移植瘤小鼠的肿瘤生长，抑制小鼠肺转移，延长小鼠手术切除皮下肿瘤后的生存时间。此外，4-羟基地黄还能抑制去瘤小鼠脾淋巴细胞、CD_4~+T、CD_8~+T和自然杀伤(NK)细胞的减少。3.新型二十碳五烯酸(EPA)衍生物及其抗肿瘤和抗转移活性的分离和结构测定EPA在加速稳定性试验过程中形成的EPA衍生物，通过抗血管生成和刺激免疫功能，抑制LLC荷瘤小鼠的肿瘤生长和肺转移。EPA衍生物由新发现的EPA乙酯二聚体和EPA羟乙酯以及已知的EPA和EPA乙酯的混合物组成。EPA乙酯二聚体和EPA羟乙酯能促进LLC细胞产生O2-，且EPA乙酯二聚体的作用强于EPA乙酯。因此，这些发现表明EPA乙酯二聚体和EPA羟基乙酯形成的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。较少

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