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

1. 我们采用原位移植方法建立了人结肠癌TK-3、-4、-6、-9、-10、-13株的肝转移模型，肝转移率为38% ~ 83%。在TK-4中发现p53点突变，在TK-13中发现p53缺失。我们可以建立稳定的肝转移模型，因为这6株菌株的初始建立是用被认为具有高恶性潜能的肝转移灶。制备了亲肝脂质体，以增强被包裹的基因进入肝脏的吸收。为了研究亲肝脂质体的有效性，我们将阿霉素（ADM）代替p53基因包埋在脂质体（lip -ADM）中。hp -ADM给药后肝脏中ADM浓度显著高于游离ADM（未包埋ADM）和cLip-ADM（包埋在对照（非亲肝）脂质体中）。在治疗效果方面，cLip-ADM使TK-4的肝转移率降低42.9%，lip - adm完全抑制TK-4的肝转移，而对照组原位移植后肝转移率为85.7%。根据前期实验结果和近期报道的研究成果，我们试图制备包埋人野生型p53质粒的脂质体，而不是核苷酸。以pRC/CMV为载体可制备人野生型p53质粒。然而，到目前为止，我们还没有发现hLip-p53（野生型p53包埋在促肝脂质体中）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验证。

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.