Radiation-induced tumour necrosis factor-alpha expression: clinical application of transcriptional and physical targeting of gene therapy.
Promising data are emerging on a new anticancer agent, Ad.EGR-TNF, an adenoviral vector, which contains radio-inducible DNA sequences from the early growth response (EGR1) gene promoter and cDNA for the gene encoding human tumour necrosis factor-alpha. Ad.EGR-TNF combines the well-documented broad-spectrum anticancer activity of TNFalpha with the proven clinical usefulness of radiotherapy. Systemic delivery of the TNFalpha protein has had limited success clinically because of severe dose-limiting toxic effects. This limitation has been overcome by the use of a gene delivery approach, combined with a radiation-inducible promoter to express the TNFalpha protein in the irradiated tumour tissue. Preclinical and early phase I clinical testing indicates that effective concentrations of TNFalpha can be delivered to the tumour site without significant systemic exposure or toxic effects. The combination of radiation and TNFalpha gene delivery has produced striking antitumour effects in model systems in animals. In the clinical setting, potent anticancer activity has been observed with a high rate of complete and partial objective tumour responses. A novel mechanism of destruction of the tumour vasculature seems to be central to this distinct antitumour activity. This review summarises the rationale, mechanistic basis, preclinical data, and preliminary clinical findings for this new treatment model.
Weichselbaum
Ralph R
RR
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. rrw@rover.uchicago.edu
Kufe
Donald W
DW
Hellman
Samuel
S
Rasmussen
Henrik S
HS
King
C Richter
CR
Fischer
Paul H
PH
Mauceri
Helena J
HJ
D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D017874:Immediate-Early Proteins; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D011839:Radiation, Ionizing; D011878:Radiotherapy; D014157:Transcription Factors / Q000096:biosynthesis*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha