Development of an adenovirus vector with tetracycline-regulatable human tumor necrosis factor alpha gene expression.
Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine with direct antitumor activity. However, clinical trials using TNF-alpha for cancer treatment have been disappointing due in part to its severe side effects, and it has been estimated that TNF-alpha therapy would be effective only at 5-25 times the maximum tolerated dose. We have recently modified a tetracycline (Tc) repressor/operator-based mammalian gene expression system and have generated a Tc-responsive recombinant adenovirus vector, AdVtTA.TNF-alpha. A variety of human tumor cells and T lymphocytes transduced by AdVtTA.TNF-alpha secreted high-titer (5,000-100,000 pg/10(6) cells/24 h) and biologically active TNF-alpha in the absence of Tc. Expression of TNF-alpha in the transduced cells was nondetectable when the culture medium contained as little as 0.1 microg/ml of Tc. At least a fraction of the clonogenic cells from human peripheral blood stem cell concentrates were also transducible by AdVtTA.TNF-alpha. The availability of this type of adenovirus vector opens a door to tumor- or organ-specific delivery of high-dose TNF-alpha and other therapeutic gene products for systemic cancer gene therapy.
Hu
S X
SX
Department of Molecular Oncology, University of Texas M.D. Anderson Cancer Center, The Woodlands 77381, USA.
Ji
W
W
Zhou
Y
Y
Logothetis
C
C
Xu
H J
HJ
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D013752:Tetracycline / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics*
D011500:Protein Synthesis Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013752:Tetracycline