Anti-tumor activity of synthetic alkyllysophospholipids and glycolipids

合成烷基溶血磷脂和糖脂的抗肿瘤活性

• 批准号: 59870076
• 负责人: KUDO Ichiro
• 金额: $ 9.15万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research
• 财政年份: 1984
• 资助国家: 日本
• 起止时间: 1984 至 1986
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-59870076/
• 关键词: Alkylphospholipids; glyceroglycolipids; macrophage; platelet activating factor; 抗腫瘍活性; リゾリン脂質; 糖脂質

(1) Alkylphospholipids1-0-Octadecyl-2-0-methyl-glycero-3-phosphocholine (ET18-0Me) has been reported to prossess difine anti-tumor effect in vivo. Lysophospholipid analogs were chemically synthesized and their anti-tumor activity against mouse experimental tumor (Sarcoma 180, MM46) were examined. Among them, 1-0-octadecy-2-0-acetoacetyl-glycero-3-phosphocholine was found to show anti-tumor activity similar to ET18-0Me, with less acute toxicity.Intravenous injection of the ET18-0Me with sn-3 configuration retarded the subcutaneous growth of Sarcoma 180 cells effectively, while the growth inhibition by the sn-1 isomer was much less effective. This stereospecificity was similar to that observed in their activities as PAF agonist. The acetoacetyl compound, another PAF aganist, showed similar stereospecific anti-tumor action in vivo. These findings suggest that some alkyl lysophospholipids may activate host cells to a cytostatic stage against tumor cells in vivo through binding to a PAF rec … More eptor. Our preliminary result indicated that the responsible cells under these conditions might primarily be immature macrophages present in the bone-marrow.On the other hand, under some conditions, the in vivo anti-tumor activity of ET18-0Me may be revealed through direct cytotoxicity and/or modulation of host defense system by 'non-specific' mechanisms.(2) GlycolipidsLiposomes composed of chemically synthesized glyceroglycolipids, such as 1,2-dipalmityl-[ <beta> -cellobiosyl-(1'->3)]-glycerol (Cel-DAG), were found to enhance protective immunity against transplatable tumor cells (sarcoma 180) in ICR mice. Peritoneal exudate cells prepared from mice treated in vivo with Cel-DAG showed cytostatic activity in vivo against the mouse leukemia cell line, EL-4. Adherent cells separated from this preparation showed similar activity.The adherent cell fraction alone showed rather weak cytostatic activity when pretreated with the glyceroglycolipids, and full activity was restored by supplementing with the non-adherent cell fraction. The ability of glycolipids to induce tumoricidal effects was affected by cholesterol content: with increasing cholesterol content, the activities decreased. Less

(1)烷基磷脂-0-十八烷基-2-0-甲基-甘油-3-磷酸胆碱（ET18-0Me）在体内有明确的抗肿瘤作用。化学合成溶血磷脂类似物，并检测其对小鼠实验性肿瘤（肉瘤180、MM46）的抗肿瘤活性。其中，1-0-十八烷基-2-0-乙酰乙酰-甘油-3-磷酸胆碱具有与ET18-0Me相似的抗肿瘤活性，但急性毒性较小。静脉注射具有sn-3构型的ET18-0Me可有效延缓肉瘤180细胞的皮下生长，而sn-1异构体的生长抑制作用要弱得多。这种立体特异性与它们作为PAF激动剂的活性相似。另一种PAF拮抗剂乙酰乙酰基化合物在体内表现出类似的立体特异性抗肿瘤作用。这些发现表明，一些烷基溶血磷脂可能通过与PAF受体结合，在体内激活宿主细胞，使其进入抗肿瘤细胞的细胞抑制阶段。我们的初步结果表明，在这些条件下负责的细胞可能主要是骨髓中存在的未成熟巨噬细胞。另一方面，在某些条件下，ET18-0Me的体内抗肿瘤活性可能通过直接的细胞毒性和/或通过“非特异性”机制调节宿主防御系统来揭示。(2)糖脂：由化学合成的甘油糖脂组成的脂质体，如1,2-双棕榈酰-[< β -> -纤维素生物基-(1'- bbb3)]-甘油（cell - dag），可增强ICR小鼠对可移植肿瘤细胞（肉瘤180）的保护性免疫。经细胞- dag处理的小鼠腹膜渗出细胞在体内对小鼠白血病细胞系EL-4表现出细胞抑制活性。从该制剂中分离出的贴壁细胞表现出类似的活性。单独贴壁细胞部分经甘油脂预处理后表现出较弱的细胞抑制活性，补充非贴壁细胞部分后恢复完全活性。糖脂诱导肿瘤杀伤作用的能力受胆固醇含量的影响：随着胆固醇含量的增加，活性降低。少

项目成果

H.Hayashi, I.Kudo, K.Inoue: "Induction by PAF and its agonists of cytolytic activity in murine bone marrow cells"

H.Hayashi、I.Kudo、K.Inoue：“PAF 及其激动剂对小鼠骨髓细胞的细胞溶解活性的诱导”

内藤幹彦,工藤一郎,向井(佐藤)幸子,津島進,野村容朗,野島庄七,井上圭三: Cancer Immunology and Immunotherapy. (1987)

Mikihiko Naito、Ichiro Kudo、Sachiko Mukai（Sato）、Susumu Tsushima、Yoro Nomura、Shoshichi Nojima、Keizo Inoue：癌症免疫学和免疫治疗（1987）。

H.Hayashi, I.Kudo, I.Kondo, K.Inoue: "Specific binding sites for PAF on macrophages and bone marrow cells from various species"

H.Hayashi、I.Kudo、I.Kondo、K.Inoue：“PAF 在不同物种的巨噬细胞和骨髓细胞上的特异性结合位点”

工藤一郎,野島庄七,張げんきょう,矢ノ下良平,林秀敏,近藤絵理,津島進,奥谷哲哉,野村容朗,井上圭三: Lipids. (1987)

工藤一郎、野岛祥七、张玄协、柳下良平、林秀俊、近藤绘里、津岛进、奥谷哲也、野村养老、井上圭三：脂质（1987）。

I.Kudo, S.Nojima, H.W.Chang, R.Yanoshita, H.Hayashi, E.Kondo, S.Tsushima, T.Okutani, H.Nomura K.Inoue: "Anti-tumor activity of synthetic alkylphospholids with or without PAF activity" Lipids. (1987)

I.Kudo、S.Nojima、H.W.Chang、R.Yanoshita、H.Hayashi、E.Kondo、S.Tsushima、T.Okutani、H.Nomura K.Inoue：“含或不含 PAF 的合成烷基磷脂的抗肿瘤活性