Cationic Liposome-Mediated p53 Gene Therapy in Liver Cancers: Result of Basic and Clinical Study
저자
Moon,Young Ho (Biotechnology Research Institute, Sung-Ae Hospital) ; Kim,Byung Koo (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Shim,Hyung Jin (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Uhm,Tae Han (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Cha,Sung Jae (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Moon,Chul So (Department of Physiology and Human Genetics, Johns Hopkins Medical School) ; Moon,Woo-Chul (Department of Internal Medicine and Radiology, National Medical Center) ; Kwak,Byung Kook (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Gi,Young Jin (Department of Internal Medicine and Radiology, National Medical Center) ; Lim,Hyun Mook (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Yoo,Nam Sook (Deparment of Urology, General Surgery and Radiology, Chung-Ang University Hospital) ; Lee,Chang Joon (Department of Internal Medicine and Radiology, National Medical Center)
발행기관
학술지명
권호사항
발행연도
1998
작성언어
English
KDC
513
자료형태
학술저널
수록면
103-112(10쪽)
제공처
p53 is a prototype tumor suppressor gene, which plays key roles in regulation of cell cycle progression, apoptosis, DNA repair and maintenance of genomic stability. Experimental stydy study on p53 gene therapy for cancer have been widely tried and Success of adenovirus or retrovirus-mediated p53 gene therapy have been reported in patients with lung cancer and cancer of the head and neck. However, viral vector-mediated gene therapy may have demerits to be widely applied in human cancers. We herein have designed a cationic liposome-mediated p53 gene therapy and have studied its antitumor efficacy and safety in vitro, in vivo and in human patients with advanced liver cancers.
We constructed and prepared a complex of plamid vector carrying cDNA of human wild type(WT) p53, cationic liposome (HECH : DOPE) and cationic polymer (polylysine) in sterile and endotoxin-free condition depending on the guideline of FDA and used this complex for in vitro and in vivo transfer oi WT p53 gene. In vitro administration of p53 gene to a variety of human cancer cells with point mutation or deletion of p53 in DNA dose of 1㎍ per ?? cells induced high level expression of WT p53 and p21/WAF1 as demonstrated by RT-PCR-Southern blot and Western blot, apoptosis as demonstrated by DNA electrophoresis, and significant decrease of viable cell numbers by 70.4 to 98.5%, whereas, administration of p53 gene in same condition to human cancer cells with WT p53 didn't induce either apoptosis or significant decrease of viable cell numbers. In vivo antitumor efficacy of p53 gene transfer was initially analyzed in sc,ip, subrenal capsular and intrahepatic xenograft model of human cancers with deletion of p53. Local, ip, or iv administration of p53 gene in DNA dose of 100㎍ daily for 5 to 10 days induced expression of WT p53 and p21 in tumor tissues, significant decrease of tumor volume (by 62.0 to 99.5%)and/or incidence of tumors, and complete suppression of metastasis. Intravenous administration of p53 gene in DNA dose of up to 12 mg/kg to rats didn't induce significant acute or sub-acute toxicity as demonstrated by survival body weight, laboratory studies, and histologic analysis of vital organs. Trans-hepatic arterial administration of p53 in DNA dose of 0.5 to 5 mg per kg induced expression of human WT p53 in rabbits liver and/or lung and didn't induce significant hepatic toxicity or systemic toxicity. Trans-hepatic arterial administration of p53 gene in DNA dose of 1 mg per kg induced significant decrease of tumor incidence (to 40%) and volume (to 0.4% of control) and suppression of metastasis of rabbits liver VX2 carcinoma which carry point mutation of p53. These results suggested that our cationic polyliposome-mediated p53 gene trasfer might be a promising treatment modality for human cancers which carry mutation of p53.
Based on the results of basic research, we carried out a pilot study to investigate antitumor efficacy and safety of cationic liposome-mediated p53 gene therapy in patients with liver cancer. Patients whth advanced, primary (N=12) or metastatic (N=4) liver cancer who had failed conventional therapy underwent p53 gene therapy, of whom 12 showed mutation of p53. Patients with advanced liver cirrhosis or metastasis were also included in the study. Fifteen patients with advanced liver cancer who underwent hepatic angiography alone served as control. p53 gene was administered in complex with HECH : DOPE : PLL into common hepatic artery in DNA dose of 10 to 30 mg every 3 to 4 weeks for 2 to 8 times (mean 4 times). Of 16 patients who underwent p53 gene therapy, 6 showed partial response, 4 minimal response and 3 stable disease. High level expression of WT p53 or p21 were found in tumor tissues of hepatovectin1 administered patients. After p53 gene therapy, 11 of 16 patients developed transient fever and chill, but none developed transient fever and chill, but none developed grade 4 toxicity or deterioration of liver function. Of 16 patients who underwent p53 gene therapy, 7 were alive on 1 year follow up and 9 died from metastatic cancer or liver cirrhosis-related complications. in contrast, none of control group survived for 1 year. These results suggest that cationic liposome-mediated p53 gene trasfer via hepatic artery may become a promising therapeutic modality for advanced liver cancer which carry mutation of p53 gene.
Our studies strongly suggest that our cationic liposome-mediated p53 gene therapy may be a promising treatment modality for human cancers which carry mutation of p53 gene and failed by conventional therapies. Further stydies are necessary on the actual benefit of this experimental study and effective systemic delivery method of p53 gene.
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