Development of anti-metastatic agents related to the early event of metastasis : screened by novel imaging thchnique.

与早期转移事件相关的抗转移剂的开发：通过新型成像技术进行筛选。

• 批准号: 07557158
• 负责人: OKADA Shoji
• 金额: $ 6.78万
• 依托单位: UNIVERSITY OF SHIZUOKA
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557158/
• 关键词: cancer metastasis; positron CT (PET); diagnostic imaging; anti-metastasis; long circulating liposomes; cancer therapy; laser; セレクチン; ポジトロンCT (PET)

Metastasis is established by a complex cascade of activities, and adhesion of tumor cells to endothelia or to extracellular matrix is one of the critical steps in the metastatic cascade. Therefore, agents that suppress such interaction may serve as anti-metastatic drugs. We previously established a non-invasive method to determine metastatic tumor cell trafficking by use of positron emission tomography (PET). In this method, positron-labeled metastatic cells are injected into bloodstream to determine tumor cell biodistribution in real-time from immediately after injection in a living animal. In here, to elucidate the involvement of cellular surface adhesion molecules in metastatic process, we investigated the effect of liposomalized sialyl Lewis X (sLe^x) as well as RGD-related peptide on the trafficking of B16BL6 melanoma cells and on metastatic potential. The trafficking of the cells after injection into tail vein was highly affected by liposomal sLe^x, but only little by RGD-related peptide, suggesting adhesion of metastatic cells to the target is initially mediated via selectin, and integrin-mediated adhesion may occur the later stages. Furthermore, liposomal sLe^x suppressed experimental metastasis suggesting that adhesion via selectin is important step for metastasis. Next to enhance the metastasis-suppressing efficacy, liposomalizaton of RGD was attempted, since RGD-related peptides have been found to suppress metastasis. Various structures of RGD analogs grafted to hydrophobic groups were systhesized and then incorporated into liposomes. Some of liposomalized RGD markedly inhibited lung colonization at the concentration of an order of magnitude lower than that for comparable inhibition reported for free RGD.The present study indicate that liposomal application is useful for both clarifying metastasis mechanism and development of anti-metastatic pharmaceutics.

转移是通过一系列复杂的活动建立的，肿瘤细胞与内皮细胞或细胞外基质的粘附是转移级联反应中的关键步骤之一。因此，抑制这种相互作用的药剂可以用作抗转移药物。我们以前建立了一个非侵入性的方法来确定转移性肿瘤细胞的运输使用正电子发射断层扫描（PET）。在该方法中，将正电子标记的转移性细胞注射到血流中，以在活体动物中注射后立即实时确定肿瘤细胞的生物分布。在这里，为了阐明细胞表面粘附分子在转移过程中的参与，我们研究了脂质体化的sialyl刘易斯X（sLe^x）以及RGD相关肽对B16 BL 6黑色素瘤细胞的运输和转移潜力的影响。注射到尾静脉后，细胞的运输受到脂质体sLe^x的高度影响，但仅受RGD相关肽的影响很小，表明转移细胞与靶标的粘附最初是通过选择素介导的，而整合素介导的粘附可能在后期发生。此外，脂质体sLe^x抑制实验转移，表明经由选择素的粘附是转移的重要步骤。其次，为了增强转移抑制功效，尝试了RGD的脂质体化，因为已经发现RGD相关肽抑制转移。合成了各种结构的接枝到疏水基团上的RGD类似物，然后掺入脂质体中。部分脂质体化的RGD在浓度低于游离RGD的水平时，可显著抑制肺癌细胞的肺定植，这一研究结果表明脂质体的应用有助于阐明肺癌转移机制和开发抗转移药物。

项目成果

Chieko koike, Noato Oku, Manabu Watanabe, Hideo Tsukada, Takeharu Kakiuchi, Tatsuro Irimura, and Shoji Okada: "Real-time PET Analysis of Metastatic Tumor Cell Trafficking in Vivo and Its Relation to Adhesion Properties" Biochim.Biophys.Acta. 1238. 99-106

Chieko koike、Noato Oku、Manabu Watanabe、Hideo Tsukada、Takeharu Kakiuchi、Tatsuro Irimura 和 Shoji Okada：“体内转移性肿瘤细胞运输的实时 PET 分析及其与粘附特性的关系”Biochim.Biophys.Acta。

Naoto Oku, Yoshihiro Tokudome, Chieko Koike, Naoyuki Nishikawa, Hideto Mori, Ikuo Saiki and Shoji Okada: "Liposomal Arg-Gly-Asp Analogs Effectively Inhibit Metastatic B16 Melanoma Colonization in Murine Lungs" Life Sci.58. 2263-2270 (1996)

Naoto Oku、Yoshihiro Tokudome、Chieko Koike、Naoyuki Nishikawa、Hideto Mori、Ikuo Saiki 和 Shoji Okada：“脂质体 Arg-Gly-Asp 类似物有效抑制小鼠肺部转移性 B16 黑色素瘤定植”Life Sci.58。

Oku, N. et al.: "Application of Liposomes for Cancer Metastasis" Adv. Drug Delivary Rev.(in press). (1997)

Oku, N. 等人：“脂质体在癌症转移中的应用”Adv。

Saiki, I.et al.: "Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor cell arrest in lungs followed by extravasation." Int.J.Cancer. 65. 833-839 (1996)

Saiki, I.等人：“唾液酸路易斯 X 和纤连蛋白衍生的 RGDS 肽类似物对肺部肿瘤细胞停滞和外渗的功能作用。”

Oku,N.et al.: "Application of Liposomes for Cancer Metastasis" Adv.Drug Delivery Rev.(in press). (1997)

Oku,N.等人：“脂质体在癌症转移中的应用”Adv.Drug Delivery Rev.（正在印刷中）。