ANTIFUMOR EFFECT OF OLIGONUCLEOTIDE ENTLRAPPED-LIPOSOMES AGAINST THE DIGESTRE ORGAN CANCER.

寡核苷酸包埋脂质体对消化器官癌的抗肿瘤作用。

• 批准号: 05671001
• 负责人: KONNO Hiroyuki
• 金额: $ 1.41万
• 依托单位: HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671001/
• 关键词: LIPOSOMES; ORTHOTOPICAL TRANSPLANTATION; COLON CANCER; p53; LIVER METASTASIS; 肝転移モデル; オリゴヌクレオチド; P53

1. We established the liver metastatic model of human colon cancer strains, TK-3, -4, -6, -9, -10, -13 by using orthotopical transplantation, in which liver metastatic rate was from 38% to 83%. The point mutation of p53 was observed in TK-4 and the deletion of p53 was observed in TK-13. We could establish the stable liver metastatic model, because liver metastatic lesions, which were considered to have high malignant potential, were used for initial establisjhment of the 6 strains.2. Hepatotropic liposomes were prepared to enhance the uptake of entrapped genes into liver. To investigate the usefulness of hepatotropic liposomes, adriamycin (ADM) instead of p53 genes was entrapped in to liposomes (hLip-ADM). ADM concentration of the liver after the administration of hLip-ADM was significantly higher than that after administration of free ADM (unentrapped ADM) or cLip-ADM {ADM entrapped in control (non-hepatotropic) liposome}. Regarding the therapeutic effect, the administration of cLip-ADM decreased the liver metastasis to 42.9% and hLip-ADM inhibited the liver metastasis of TK-4 completely, whereas liver metastasis developed in 85.7% of the control after orthotopical transplantation.3. We have been tried to prepare the liposomes entrapped the human wild type p53 plasmid, instead of nucreotides, based on the results of our preliminary experiments and the studies reported recently. The human wild type p53 plasmid could be prepared by using pRC/CMV as the vector. However, we can not show the therapeutic effect of hLip-p53 (wild type p53 entrapped in hepatotropic liposome) on liver metastasis, so far. Antiproliferative effect and antimetastatic effect of hLip-p53 will be examined in the in vitro and in vivo experiments.

1.采用原位移植技术建立了人结肠癌株TK-3、-4、-6、-9、-10、-13的肝转移模型，其肝转移率为38%～83%。 TK-4中观察到p53点突变，TK-13中观察到p53缺失。由于6株菌株的初步建立均采用了恶性程度较高的肝转移灶，因此可以建立稳定的肝转移模型。 2．制备亲肝脂质体以增强肝脏对包埋基因的摄取。为了研究亲肝脂质体的有用性，将阿霉素 (ADM) 代替 p53 基因包埋到脂质体 (hLip-ADM) 中。施用hLip-ADM后肝脏的ADM浓度显着高于施用游离ADM(未包埋的ADM)或cLip-ADM{包埋在对照(非亲肝性)脂质体中的ADM}后的肝脏ADM浓度。就治疗效果而言，cLip-ADM给药使肝转移减少至42.9%，hLip-ADM完全抑制TK-4肝转移，而原位移植后肝转移发生率为85.7%。 3．根据我们的初步实验结果和最近报道的研究结果，我们尝试制备包埋人野生型p53质粒而不是核苷酸的脂质体。以pRC/CMV为载体，可以制备人野生型p53质粒。然而，迄今为止，我们还无法证明hLip-p53（包埋在亲肝脂质体中的野生型p53）对肝转移的治疗作用。 hLip-p53的抗增殖作用和抗转移作用将在体外和体内实验中进行检测。

项目成果

Tanaka T.: "Prevention of nepatic metasis of human colon Cancer by angiogenesis inhibitor TNP-470." Can Res.55. 836-839 (1995)

Tanaka T.：“通过血管生成抑制剂 TNP-470 预防人类结肠癌的肾转移。”

Konno H.: "Intra-arerial liposomal adriamycin for metastatic adenocarcino ma of the liver." Eur.Surg.Res.27. 301-306 (1995)

Konno H.：“动脉内脂质体阿霉素治疗转移性肝腺癌。”

Konno H.: "Comparison of the inhibitory effect of angiogenesis inhibitor, TNP-470, and mitomycin C on the growth andliver metasis of human colon cancer." Int.J.Cancer. 61. 268-271 (1995)

Konno H.：“血管生成抑制剂 TNP-470 和丝裂霉素 C 对人结肠癌生长和肝转移的抑制作用比较。”

Konno H.: "Efficacy of an angiogenesis inhibitor, TNP-470, in xenotransplanted human colorectal cancer with high metastatic potential" Cancer. 77 (in press). (1996)

Konno H.：“血管生成抑制剂 TNP-470 在具有高转移潜力的异种移植人类结直肠癌中的功效”癌症。

Konno,H: "Efficacy of an angiogenesis inhibitor, TNP-470, in xenotransplanted human colcrectal cancer with high metastatic potential." Cancer. 77(in press). (1996)

Konno,H：“血管生成抑制剂 TNP-470 在具有高转移潜力的异种移植人类结肠直肠癌中的功效。”