Heat-induced gene expression as a novel targeted cancer gene therapy strategy.
One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we experimented with a new approach based on the long-established phenomenon of the heat shock response. By using the green fluorescence protein as a reporter gene, it was demonstrated that expression of a heterologous gene with a heat shock protein 70 promoter could be elevated to 500-1000-fold over background by moderate hyperthermia (39 degrees C to 43 degrees C) in tissue cultured cells. The heat-induced green fluorescence protein expression was first detectable at 3 h after heating and reached a maximum at 18-24 h. The expression dropped back to baseline within 72 h. In addition, when cells were infected with adenovirus vectors containing the heat-inducible interleukin 12 or tumor necrosis factor alpha genes and then heated (42 degrees C, 30 min), expression was at least 13,600- or 6.8 x 10(5)-fold over background, respectively. Intralesion injection of the interleukin-12-carrying adenovirus vector in a mouse melanoma tumor model caused significant tumor growth delay only with hyperthermia treatment. Our results therefore support heat-induced gene expression as a feasible approach for targeted cancer gene therapy.
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
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Huang
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Hu
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Lohr
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Zhang
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Braun
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Lanzen
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Little
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Dewhirst
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Li
D000256:Adenoviridae; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D011401:Promoter Regions, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D018840:HSP70 Heat-Shock Proteins; D008164:Luminescent Proteins; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D018664:Interleukin-12