Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma.
OBJECTIVE
To overcome radiation resistance in esophageal adenocarcinoma by tumor-specific apoptotic gene targeting using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).


METHODS
Adenoviral vector Ad/TRAIL-F/RGD with a tumor-specific human telomerase reverse transcription promoter was used to transfer TRAIL gene to human esophageal adenocarcinoma and normal human lung fibroblastic cells (NHLF). Activation of apoptosis was analyzed by Western blot, fluorescent activated cell sorting, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate labeling (TUNEL) assay. A human esophageal adenocarcinoma mouse model was treated with intratumoral injections of Ad/TRAIL-F/RGD plus local radiotherapy.


RESULTS
The combination of Ad/TRAIL-F/RGD and radiotherapy increased the cell-killing effect in all esophageal adenocarcinoma cell lines but not in NHLF cells. This combination also significantly reduced clonogenic formation (p < 0.05) and increased sub-G1 deoxyribonucleic acid accumulation in cancer cells (p < 0.05). Activation of apoptosis by Ad/TRAIL-F/RGD plus radiotherapy was demonstrated by activation of caspase-9, caspase-8, and caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase in vitro and TUNEL assay in vivo. Combined Ad/TRAIL-F/RGD and radiotherapy dramatically inhibited tumor growth and prolonged mean survival in the esophageal adenocarcinoma model to 31.6 days from 16.7 days for radiotherapy alone and 21.5 days for Ad/TRAIL-F/RGD alone (p < 0.05).


CONCLUSIONS
The combination of tumor-specific TRAIL gene targeting and radiotherapy enhances the effect of suppressing esophageal adenocarcinoma growth and prolonging survival.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jychang@mdanderson.org
Joe Y
JY
Chang
Xiaochun
X
Zhang
Ritsuko
R
Komaki
Rex
R
Cheung
Bingliang
B
Fang
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D004938:Esophageal Neoplasms / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000235:genetics*; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000627:therapeutic use*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha