New targeting therapy with complex of liposome, consist of comparable lipid composition of oral cancer cells, and anti-EGF receptor antibody.

采用脂质体复合物的新型靶向治疗，由口腔癌细胞的相似脂质成分和抗 EGF 受体抗体组成。

• 批准号: 10557191
• 负责人: TORATANI Shigeaki
• 金额: $ 3.78万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557191/
• 关键词: anti-cancer drugs; liposome; anti-EGF receptor antibody; lipid composition; squamous cell; adenocarcinoma derived; 膜脂質組成; 扁平上皮癌細胞

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, peplomycin doxorubicin and paclitaxel of five human cancer cell lines by growth assay in serum-free culture. Of the cell line tested, salivary gland adenocarcinoma cell lines(SAC) were shown to be generally more sensitive to cisplatinand paclitaxal than squamous cell carcnoma cell lines (SCC) in vitro, and SCC were relatively resistant to cisplatine. On the other hand SCC were more sensitive to peplomycin and doxorubicin in comparison to SAC. It is known that cisplatin, peplomycin and doxorubicin were uptaken in the cells by passive transport system. We have speculated that heterogeneity of these anti-cancer drug effects is correlated with intracellular drug levels, resulted from the difference of membrane permeability of cancer cells. We studied the membrane lipid composition of the cell lines in serum-free medium w … More hich determine the membrane permeability. We have found that 70% of total membrane lipid in SCC is phospholipid and remainder is free cholesterol. On the other hand, 80% of total membrane lipid in SAC is neutral lipid such as triglyceride and esterified cholesterol and 20% is phosholipid. The higher neutral lipid level of SAC which should have resulted in decreased membrane fluidity, is consistent with the higher accumulation of cisplatin compared SCC. On the other hand, peplomycin and doxorubicin exhibited high cytotoxicity to SCC, which membrane lipid consisted of phospholipid main]y and the membrane fluidity was higher than that of SAC. These results suggest that the lipid composition of cancer cell membrane is major factor determining the sensitivity of cancer cells to cisplatin, peplomycin, doxorubicin and paclrtaxel Thus we have designed liposome which is comparable to the lipid composition of SCC cell membrane, constructed the liposome-entrapped cisplatin or peplomycin and examined sensitivity to the liposome-entrapped drug of both SCC and SAC by growth assay in serum-free culture. As the result, the liposome-entrapped drug exhibited enhanced cytotoxicity on SCC compare to either drug alone or drug-liposome mixture. Furthermore it is known that the epidermal growth factor (EGF) receptor overexpress on SCC and SAC. So we prepared antibody to anti-EGF receptor (12-93 MoAb) and examined the cytotoxic effect of the CDDP-entapped liposome conjugated with 12-93 MoAb to NA and HSY. As result, this complex shown enhanced high cytotoxicity to NA and HSY compare CDDP alone. Less

长期以来，人们已经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检测了五种人癌细胞系对顺铂、培洛霉素、阿霉素和紫杉醇的敏感性。体外实验结果表明，涎腺腺癌细胞系（SAC）对顺铂和紫杉醇的敏感性高于鳞状细胞癌细胞系（SCC），而SCC对顺铂的耐药性相对较强。另一方面，SCC对培洛霉素和多柔比星比SAC更敏感。已知顺铂、培洛霉素和多柔比星通过被动转运系统被细胞摄取。我们推测，这些抗癌药物作用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。我们研究了细胞系在无血清培养基中的膜脂组成， ...更多信息 其确定膜渗透性。我们发现SCC中70%的膜脂为磷脂，其余为游离胆固醇。另一方面，SAC中总膜脂的80%是中性脂质，如甘油三酯和酯化胆固醇，20%是磷脂。SAC的中性脂质水平较高，这应该导致膜流动性降低，与SCC相比顺铂的蓄积较高一致。而培洛霉素和阿霉素对以磷脂为主的SCC细胞具有较强的细胞毒作用，SCC细胞膜流动性高于SAC。这些结果表明，癌细胞膜的脂质组成是决定癌细胞对顺铂，培洛霉素，阿霉素和紫杉醇的敏感性的主要因素。因此，我们设计了脂质体，这是与SCC细胞膜的脂质组成，构建了脂质体包载顺铂或培洛霉素，并通过无血清培养的生长试验检测SCC和SAC对脂质体包载药物的敏感性。结果表明，脂质体包封的药物对SCC的细胞毒性比单独药物或药物-脂质体混合物增强。此外，已知表皮生长因子（EGF）受体在SCC和SAC上过表达。因此，我们制备了抗EGF受体抗体（12-93 MoAb），并检测了12-93 MoAb偶联的CDDP包封脂质体对NA和HSY的细胞毒作用。结果表明，该复合物对NA和HSY的细胞毒性比单独的CDDP更强。少

项目成果

S.Tratani et al.: "Effect of photodynamic therapy aetion with pheopharbide-a on human oral carcinoma cells in serum-free culture"Tiss.Cult.Res.Commun.. 18. 345-352 (1999)

S.Tratani 等人：“脱镁叶绿酸-a 光动力疗法对无血清培养物中人口腔癌细胞的影响”Tiss.Cult.Res.Commun. 18. 345-352 (1999)

S. Toratani, N. Kimoto, T. Shinki and T. Okamoto: "Effect of photodynamic action with pheophorbide-a on human oral carcinoma cells in serum-free culture."Tiss. Cult. Res. Commun.. 18. 345-352 (1999)

S. Toratani、N. Kimoto、T. Shinki 和 T. Okamoto：“脱镁叶绿酸-a 的光动力作用对无血清培养物中人口腔癌细胞的影响。”Tiss。

S. Toratani et al.: "Effect of photodynamic therapy action with pheophorbide-a on human oral carcinoma cells in serum-free culture"Tiss. Cult. Res. Commun.. 18・4. 345-352 (1999)

S. Toratani 等：“脱镁叶绿酸-a 对无血清培养物中的人口腔癌细胞的影响”Tiss Commun. 18・4 (1999)。