Selective gene expression using a DF3/MUC1 promoter in a human esophageal adenocarcinoma model.
The efficacy of replication-deficient adenoviral vectors in gene therapy is confined to the number of tumor cells the vector infects. To focus and enhance the therapeutic efficacy, we employed a conditionally replication-competent adenoviral vector with a tissue-specific promoter, DF3/MUC1, in a human esophageal adenocarcinoma model. Our results demonstrate that Ad.DF3.E1A.CMV.TNF (Ad.DF3.TNF) specifically replicates in Bic-1 (DF3-producing cells) and mediates an enhanced biologic effect due to increased TNF-alpha in the same DF3-producing cells. We also show that the increased TNF-alpha interacts with ionizing radiation to produce greater tumor regression and a greater delay in tumor regrowth in Bic-1 (DF3-producing cells) compared to Seg-1 (DF3 non-producers). Tumor cell targeting using conditionally replication-competent adenoviral vectors with tumor-specific promoters to drive viral replication and deliver TNF-alpha provides a novel approach to enhancing tumor radiosensitivity.
Gupta
V K
VK
Department of Surgery, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Park
J O
JO
Kurihara
T
T
Koons
A
A
Mauceri
H J
HJ
Jaskowiak
N T
NT
Kufe
D W
DW
Weichselbaum
R R
RR
Posner
M C
MC
D000230:Adenocarcinoma / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D018396:Mucin-1 / Q000032:analysis / Q000235:genetics*; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011897:Random Allocation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014779:Virus Replication
D008164:Luminescent Proteins; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins