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Heat-inducible in vivo gene therapy of colon carcinoma by human mdr1 promoter-regulated tumor necrosis factor-alpha expression

Item Type:Article
Title:Heat-inducible in vivo gene therapy of colon carcinoma by human mdr1 promoter-regulated tumor necrosis factor-alpha expression
Creators Name:Walther, W. and Arlt, F. and Fichtner, I. and Aumann, J. and Stein, U. and Schlag, P.M.
Abstract:The promoter of the human multidrug resistance gene (mdr1) harbors defined heat-responsive elements, which could be exploited for construction of heat-inducible expression vectors. To analyze the hyperthermia inducibility of the mdr1 promoter in vitro and in vivo, we used the pcDNA3-mdrp-hTNF vector construct for heat-induced tumor necrosis factor {alpha} (TNF-{alpha}) expression in transfected HCT116 human colon carcinoma cells at mRNA level by quantitative real-time reverse transcription-PCR and at protein level by TNF-{alpha} ELISA. For the in vitro studies, the pcDNA3-mdrp-hTNF–transfected tumor cells were treated with hyperthermia at 43°C for 2 h. In the animal studies, stably transfected or in vivo jet-injected tumor-bearing Ncr:nu/nu mice were treated for 60 min at 42°C to induce TNF-{alpha} expression. Both the in vitro and in vivo experiments show that hyperthermia activates the mdr1 promoter in a temperature- and time-dependent manner, leading to an up to 4-fold increase in mdr1 promoter–driven TNF-{alpha} expression at mRNA and an up to 3-fold increase at protein level. The in vivo heat-induced TNF-{alpha} expression combined with Adriamycin (8 mg/kg) treatment leads to the inhibition of tumor growth in the animals. These experiments support the idea that heat-induced mdr1 promoter–driven expression of therapeutic genes is efficient and feasible for combined cancer gene therapy approaches.
Keywords:Hyperthermia, mdr1 Promoter, TNF-{alpha}, Gene Therapy, Colon Cancer, Animals, Mice
Source:Molecular Cancer Therapeutics
Publisher:American Association for Cancer Research
Page Range:236-243
Date:January 2007
Official Publication:https://doi.org/10.1158/1535-7163.MCT-06-0070
PubMed:View item in PubMed

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