RRC ID 2045
Author Terazaki Y, Yano S, Yuge K, Nagano S, Fukunaga M, Guo ZS, Komiya S, Shirouzu K, Kosai K.
Title An optimal therapeutic expression level is crucial for suicide gene therapy for hepatic metastatic cancer in mice.
Journal Hepatology
Abstract The most serious problem in current gene therapy is discrepancies between experimental data and actual clinical outcomes, which may be due to insufficient analyses and/or inappropriate animal models. We have explored suicide gene therapy by using various clinically relevant animal models and doubt the clinical use of maximal suicide gene expression, which has been generally recommended. To explore this subject further, we studied what expression level of suicide gene and what promoter led to the maximal clinical benefit in the case of hepatic metastatic cancer in mice. Therapeutic and adverse side effects of 4 adenoviral vectors that express herpes simplex virus thymidine kinase (HSV-tk) under different promoters were scrupulously investigated in 2 mouse models of hepatic metastasis of gastric cancer that possess clinical characteristics. Surprisingly, increases in HSV-tk expression beyond a certain point, achieved by the Rous sarcoma virus long terminal repeat promoter, not only enhanced the adverse side effects of lethal hepatotoxicity and ganciclovir-independent cytotoxicity but also failed to further increase therapeutic potential. Moreover, the carcinoembryonic antigen (CEA) tumor-specific promoter, the therapeutic potential of which had been underestimated, was much more useful-even in the case of low CEA-producing cancer-than had been previously reported. In conclusion, the optimal therapeutic expression level of a suicide gene is a novel concept and a crucial factor for successful cancer gene therapy. The present results, which contradict those of previous studies, alert researchers about possible problems with ongoing and future clinical trials that lack this concept.
Volume 37(1)
Pages 155-63
Published 2003-1
DOI 10.1053/jhep.2003.50018
PII S0270913902141322
PMID 12500200
MeSH Adenoviridae / genetics Animals Carcinoembryonic Antigen / analysis Disease Models, Animal Gene Expression Genetic Therapy / adverse effects* In Vitro Techniques Liver Neoplasms / secondary Liver Neoplasms / therapy* Male Mice Mice, Inbred BALB C Mice, Nude Neoplasm Transplantation Promoter Regions, Genetic Simplexvirus Stomach Neoplasms / pathology Thymidine Kinase / genetics Transduction, Genetic Tumor Cells, Cultured / chemistry
IF 14.971
Times Cited 30
WOS Category GASTROENTEROLOGY & HEPATOLOGY
Resource
DNA material AxCAHSVtk (RDB02547)