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Development of new drug deliverty system with liposome consist of comparable to the lipid composition of oral cancer cancer cell membrane

开发新的脂质体药物递送系统，其组成与口腔癌癌细胞膜的脂质成分相当

基本信息

批准号：
08672311
负责人：
TORATANI Shigeaki
金额：
$ 1.47万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

It has long been known that the effect of anti-cancer drug is dependent on the histological type of the target cancer cells. We have examined the sensitivity to cisplatin, doxorubicin and peplomycin of five human cancer cell lines by growth assay in serum-free culture. Of the cell line tested, slivary gland adenocarcinoma cell lines (SAC) were shown to be generally more sensitive to cisplatin than squmous cell carcinoma cell lines (SCC) in vitro, and SCC were relatively resistant to cisplatin. On the other hand, SCC were more sensitive to doxorubicin and peplomycin in comparison to SAC.It is known that cisplatin, peplomycin and doxorubicin were uptake in the cells by passive transport system. We have speculated that heterogeneity of these anticancer drug effects is correlated with intracellular drug level, resulted from the difference of membrane permiability of cancer cells. We studied the membrane lipid composition of the cell lines in serum-free medium, which determine the membrane … More permiability. We have found that 70% of total membrane lipid in SCC is phosholipid and remainder is free cholesterol. On the other hand, 80% of total membrane lipid in SAC in neutral lipid such as triglyceride and esterified cholesterol, and 20% is phospholipid. The higher neutral lipid level of SAC which should have resulted in decreased membrane fluidity, is consistent with the higher accumulation of cisplatin compared to SCC.On the other hand, doxorubicin and peplomycin exhibited high cytotoxicity to SCC,which membrane lipid consisted of phospholipid mainly and the membrane fluidity was higher than that of SAC.These result suggest that the lipid composition of cancer cell membranes is major factor determining the sensitivity of cancer cells to cisplatin, peplomycin and doxorubicin. Thus, we have designed liposome which is comparable to the lipid composition of SCC cell membrane, constructed the liposome-entrapped cisplatin and examined sensitivity to the liposome-entrapped cisplatin of both SCC and SAC by growth assay in serum-free culture. As the reult, the liposome-entrapped cisplatin exhibited enhanced cytotoxicity on SCC compare to either cisplatin alone or cisplatin-liposome mixture. And we have shown that epidermal growth factor receptor (EGFR) was over-expression on SCC and SAC.Then we made monoclonal antibody (12-93) to EGFR and combined liposome-entrapped cisplatin with anti-EGFR monoclonal antibody with avidin-biotin method. We have examined sensitivity to the liposome united with anti-EGFR monoclonal antibody of both SCC and SAC in vitro. This liposome had a tendency to enhance cytotoxicity on SCC and SAC compare to liposome-entrapped cisplatin. Less

人们早就知道抗癌药物的效果取决于靶癌细胞的组织学类型。我们用无血清培养法测定了五种人癌细胞系对顺铂、阿霉素和培洛霉素的敏感性。在所测试的细胞系中，在体外，唾液腺腺癌细胞系（SAC）通常比鳞状细胞癌细胞系（SCC）对顺铂更敏感，而SCC对顺铂相对耐药。另一方面，SCC比SAC对阿霉素和培洛霉素更敏感，已知顺铂、培洛霉素和阿霉素在细胞中通过被动转运系统摄取。我们推测，这些抗癌药物效应的异质性与细胞内药物水平有关，这是由于癌细胞膜通透性的差异造成的。我们研究了无血清培养基中细胞系的膜脂组成，这决定了膜 ...更多信息可渗透性我们发现SCC中磷脂占总膜脂的70%，其余为游离胆固醇。另一方面，SAC中80%的总膜脂为中性脂质，如甘油三酯和酯化胆固醇，20%为磷脂。SAC较高的中性脂质水平应导致膜流动性降低，这与顺铂的蓄积高于SCC相一致。另一方面，阿霉素和培洛霉素对SCC表现出较高的细胞毒性，细胞膜脂主要由磷脂组成，膜流动性高于SAC，提示癌细胞膜的脂质组成是决定癌细胞增殖的主要因素。癌细胞对顺铂、培洛霉素和阿霉素的敏感性。因此，我们设计了脂质体，这是可比的脂质体组成的SCC细胞膜，构建了脂质体包埋顺铂和检查敏感性的脂质体包埋顺铂的SCC和SAC的生长测定在无血清培养。结果表明，脂质体包埋顺铂对SCC的细胞毒作用比顺铂单独或顺铂-脂质体混合物更强。本研究制备了表皮生长因子受体（EGFR）单克隆抗体（12-93），并采用亲和素-生物素法将脂质体包裹的顺铂（DDP）与抗EGFR单克隆抗体（12-93）偶联。我们在体外检测了SCC和SAC对脂质体联合抗EGFR单克隆抗体的敏感性。与脂质体包裹的顺铂相比，该脂质体具有增强对SCC和SAC的细胞毒性的趋势。少