Combined gene therapy and ionizing radiation is a novel approach to treat human esophageal adenocarcinoma.
BACKGROUND
The ability to infect tumor cells limits the antitumor effects of gene therapy. The addition of radiotherapy to treatment with Ad.Egr.TNF.11D, a replication-deficient adenovirus containing a radiation-inducible promoter, early growth response-1, and the tumor necrosis factor-alpha (TNFalpha) complementary DNA may enhance the therapeutic ratio.


METHODS
Seg-1 human esophageal adenocarcinoma cells were treated with Ad.Egr.TNF.11D with or without radiation. TNFalpha levels were quantified with enzyme-linked immunosorbent assay. Athymic nude mice bearing Seg-1 tumors were randomized to buffer, ionizing radiation, Ad.Egr.TNF.11D, and combination therapy. Tumor growth delay was used to compare treatment regimens. TNFalpha levels were measured in tumor homogenates and plasma.


RESULTS
Seg-1 cells treated with Ad.Egr.TNF.11D and ionizing radiation demonstrated increased TNFalpha levels at 72 hours compared with cells exposed to vector alone (124 +/- 0 pg/mL vs. 31.11 +/- 22 pg/mL; P =.008). In vivo, Ad.Egr.TNF.11D-treated tumors expressed low TNFalpha levels (151.5 +/- 107.11 pg/mg protein) compared with tumors receiving combined treatment (793.92 +/- 489.13 pg/mg protein; P =.067). Increased TNFalpha levels were associated with increased tumor growth delay after combined treatment (P <.05).


CONCLUSIONS
Radiotherapy enables focal stimulation of TNFalpha expression in Ad.Egr.TNF.11D-infected cells and thus improves local tumor control.
Gupta
Vinay K
VK
Department of Surgery, The University of Chicago, 5841 South Maryland Avenue, MC 5031, Chicago, IL 60637, USA.
Park
James O
JO
Jaskowiak
Nora T
NT
Mauceri
Helena J
HJ
Seetharam
Saraswathy
S
Weichselbaum
Ralph R
RR
Posner
Mitchell C
MC
D000230:Adenocarcinoma / Q000235:genetics* / Q000532:radiotherapy*; D000256:Adenoviridae; D000818:Animals; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018450:Disease Progression; D051766:Early Growth Response Protein 1; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D011878:Radiotherapy / Q000379:methods; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha