Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.
The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered by deletion in a large fraction of human tumors, including pancreatic cancer. To evaluate the potential of FHIT gene therapy, we developed recombinant adenoviral and adenoassociated viral (AAV) FHIT vectors and tested these vectors in vitro and in vivo for activity against human pancreatic cancer cells. Our data show that viral FHIT gene delivery results in apoptosis by activation of the caspase pathway. Furthermore, Fhit overexpression enhances the susceptibility of pancreatic cancer cells to exogenous inducers of apoptosis. In vivo results show that FHIT gene transfer delays tumor growth and prolongs survival in a murine model mimicking human disease.
Dumon
K R
KR
Kimmel Cancer Center, Thomas Jefferson University, Department of Surgery, Hospital of the University of Pennsylvania, Gene Therapy Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Ishii
H
H
Vecchione
A
A
Trapasso
F
F
Baldassarre
G
G
Chakrani
F
F
Druck
T
T
Rosato
E F
EF
Williams
N N
NN
Baffa
R
R
During
M J
MJ
Huebner
K
K
Croce
C M
CM
D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000235:genetics; D053938:DNA Fragmentation; D005260:Female; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000502:physiology; D009363:Neoplasm Proteins; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D020169:Caspases; D009363:Neoplasm Proteins; D011506:Proteins; D000099170:Bis(5'-adenosyl)triphosphatase