Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy.
Heat-induced therapeutic gene expression is highly desired for gene therapy to minimize side effects. Furthermore, if the gene expression is triggered by heat stress, combined therapeutic effects of hyperthermia and gene therapy may be possible. We combined TNF-alpha gene therapy driven by the stress-inducible promoter, gadd 153, with hyperthermia using magnetite cationic liposomes (MCLs). In nude mice, MCLs induced cell death throughout much of the tumor area on heating under an alternating magnetic field. This heat stress also resulted in a 3-fold increase in TNF-alpha gene expression driven by the gadd 153 promoter as compared with that of nonheated tumor. TNF-alpha gene expression was also observed in the peripheral area where the hyperthermic effect was not enough to cause cell death. The combined treatment strongly arrested tumor growth in nude mice over a 30-day period, suggesting potential for cancer treatment.
Ito
A
A
Department of Biotechnology, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan.
Shinkai
M
M
Honda
H
H
Kobayashi
T
T
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D003131:Combined Modality Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy*; D006801:Humans; D006979:Hyperthermia, Induced; D007124:Immunoenzyme Techniques; D008081:Liposomes; D008280:Magnetics / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D008081:Liposomes; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051742:Transcription Factor CHOP