Regulation and pharmacokinetics of inducible recombinant TRAIL expression.
TRAIL is a potent antitumor agent, but its potential toxicity to normal human tissues limits its clinical applications in future. Therapy of human tumors might benefit from the use of vectors enabling tight control of TRAIL expression in vivo. To this aim, we constructed an adenoviral vector carrying the RU486-dependent gene switch system for the regulable expression of recombinant TRAIL. Only was apoptotic recombinant TRAIL expressed and cytotoxicity observed upon binding of RU 486 to the inducible promoter. Expression levels and kinetics of recombinant TRAIL expression could be achieved by modulating the concentration of the inducer. As a broad implication, our data provide an alternative approach to circumvent the potential toxicity of TRAIL in future human trials and this system may be utilized to treat human cancer using a long-term expression vector.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School, Chinese Academy of Sciences, Shanghai, China.
Aiwen
A
Dong
Jie
J
Hu
Lili
L
Zhao
Huiling
H
Xu
Xinyuan
X
Liu
D000230:Adenocarcinoma / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor / Q000637:transplantation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D015735:Mifepristone