PMID- 14508100
OWN - NLM
STAT- MEDLINE
DCOM- 20040628
LR  - 20200930
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 2
IP  - 4
DP  - 2003 Jul-Aug
TI  - Radiation therapy: activation for gene transcription and the development of 
      genetic radiotherapy-therapeutic strategies in oncology.
PG  - 326-9
AB  - Radiotherapy is a widely used local and regional modality for the treatment of 
      cancer. Despite improved methods of radiation delivery, local recurrence accounts 
      for treatment failure in most patients. Radiosensitizers have been studied as one 
      approach for improving the effectiveness of radiotherapy. Few agents, however, 
      have been shown to selectively increase the anti-tumor effects of radiation. 
      Advances in our understanding of how cells respond molecularly to ionizing 
      radiation have provided opportunities for the development of new approaches that 
      selectively enhance radiotherapy of tumors. Cells respond to ionizing radiation 
      with the activation of specific early and later response genes. These findings 
      led us to the concept that promoters from these genes could be used to drive 
      therapeutic transgenes introduced into irradiated tumor cells. In this strategy, 
      designated genetic radiotherapy, radiation is combined with gene therapy, another 
      local/regional modality, to spatially and temporally control transgene expression 
      in the irradiated field. Tumor necrosis factor-alpha (TNF-alpha) was selected as 
      the transgenic protein for its potent anti-tumor activity and synergistic 
      interactions with ionizing radiation. The radio-inducible elements from the early 
      growth response-1 (EGR-1) gene promoter have been inserted upstream to a cDNA 
      encoding TNF-alpha and integrated into a replication-defective adenovirus 
      (Ad.EGR-TNF). Preclinical studies have shown that tumors infected with Ad.EGR-TNF 
      respond to radiation with induction of TNF-alpha expression and substantial 
      increases in anti-tumor activity. Importantly, local production of TNF-alpha is 
      not associated with the limiting toxicities encountered when this cytokine was 
      administered systemically. Based on these findings, radiation in combination with 
      intratumoral administration of a second generation Ad.EGR-TNF (TNFerade) has 
      completed Phase I evaluation and has entered Phase II clinical trials.
FAU - Kufe, Donald
AU  - Kufe D
AD  - Dana-Farber Cancer Institute, Harvard Medical School; Boston, Massachusetts USA. 
      Donald_Kufe@dfci.harvard.edu
FAU - Weichselbaum, Ralph
AU  - Weichselbaum R
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (EGR1 protein, human)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (Egr1 protein, mouse)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - DNA-Binding Proteins/*genetics
MH  - Early Growth Response Protein 1
MH  - Gene Expression Regulation, Neoplastic/*radiation effects
MH  - *Genetic Therapy
MH  - Genetic Vectors/genetics/radiation effects
MH  - Humans
MH  - Immediate-Early Proteins/*genetics
MH  - Mice
MH  - Neoplasms/*therapy
MH  - Recombinant Fusion Proteins/biosynthesis
MH  - Transcription Factors/*genetics
MH  - Transcription, Genetic/*radiation effects
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
RF  - 37
EDAT- 2003/09/26 05:00
MHDA- 2004/06/29 05:00
CRDT- 2003/09/26 05:00
PHST- 2003/09/26 05:00 [pubmed]
PHST- 2004/06/29 05:00 [medline]
PHST- 2003/09/26 05:00 [entrez]
AID - 495 [pii]
AID - 10.4161/cbt.2.4.495 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2003 Jul-Aug;2(4):326-9. doi: 10.4161/cbt.2.4.495.