[Development of a novel gene therapy using survivin antisense expressing adenoviral vectors].
BACKGROUND
Survivin, a novel inhibitor of apoptosis, is undetectable in normal adult tissues but becomes notably expressed in the most common human cancers, and is recognized as a potential target in anticancer therapy.


METHODS
In this study we evaluated a survivin antisense expressing replication-incompetent adenoviral vector under the control of the cytomegalovirus promoter (pAd.CMV-SAS) for cytoreductive effects in human HT-29 colon cancer cells in vitro and in vivo.


RESULTS
Infection of tumor cells with pAd.CMV-SAS caused down-regulation of survivin expression and the potential for spontaneous apoptosis in tumor cells. In contrast, pAd.CMV-SAS did not affect cell viability of normal human cells including fibroblasts. In addition, infection of tumor cells with pAd.CMV-SAS resulted in an increase of the G0/G1 phase population in the cell cycle, and increased their sensitivity to chemotherapeutic drugs in vitro. The efficacies of pAd.CMV-SAS were inversely correlated with survivin expression level. In nude mice, pAd.CMV-SAS suppressed tumor formation, as well as decreased the tumor volumes to approximately 30% of the control tumors. Furthermore, it was confirmed that the anti-tumor efficacy of pAd.CMV-SAS was also enhanced in combination with chemotherapeutic drugs in vivo.


CONCLUSIONS
These findings suggest that targeting of survivin using adenoviral antisense vectors may have a potential role in the selective therapy of colon cancer.
Yamamoto
Tetsuhisa
T
Dept. of General and Gastroenterological Surgery, Osaka Medical College.
Manome
Yoshinobu
Y
Miyamoto
Akiko
A
Tanigawa
Nobuhiko
N
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D018076:DNA, Complementary / Q000096:biosynthesis; D015536:Down-Regulation; D018390:Gene Targeting; D015316:Genetic Therapy; D005822:Genetic Vectors; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D000077022:Survivin
C107489:BIRC5 protein, human; D018076:DNA, Complementary; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D000077022:Survivin