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Treatment of pancreatic carcinoma by adenoviral mediated gene transfer of vasostatin in mice

¹ Department of Gastroenterology, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China
² Department of Biochemistry and Centre of Human Gene Therapy, Shanghai Second Medical University, Shanghai, China

Correspondence to:
Correspondence to:
Dr Y-Z Yuan
Department of Gastroenterology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China; yyz28{at}medmail.com.cn

Background: Tumour growth is angiogenesis dependent and antiangiogenesis therapy may represent a promising therapeutic option.

Aims: To evaluate the inhibitory effect of vasostatin gene mediated by a replication deficient recombinant adenovirus (Ad) on human pancreatic cancer in vivo and to investigate the mechanism of action of vasostatin.

Methods: Human umbilical vein endothelium derived ECV304 cells were infected with Ad-vasostatin and Ad-lacZ, and compared with phosphate buffered saline (PBS). MTT (3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay was used to estimate the proliferation of ECV304 cells; tube formation assay and choriallantoic membrane assay were used to evaluate angiogenesis in vivo and in vitro. Xenografted nude mice with pancreatic cancer were established to observe in vivo tumour growth suppression. Microvessel density revealed by CD31 immunohistochemical staining was measured.

Results: Growth and tube formation of ECV304 cells infected with Ad-vasostatin were suppressed significantly compared with cells infected with Ad-lacZ or cells treated with PBS. Neovascularisation in the Ad-vasostatin group was less than that in the PBS and Ad-lacZ groups, based on chorioallantoic membrane results. Volumes of pancreatic tumours in the Ad-vasostatin group were significantly smaller than those in the PBS and Ad-lacZ groups at the end of the treatment period. Microvessel density in the Ad-vasostatin group was significantly lower than that in the Ad-lacZ and PBS groups.

Conclusion: The vasostatin gene mediated by adenovirus is efficient for gene therapy for pancreatic carcinoma. Suppression of vasostatin on proliferation of vascular endothelium cells and angiogenesis may account for its effect.

Abbreviations: CAM, chorioallantoic membrane; CMV, cytomegalovirus; FBS, fetal bovine serum; MOI, multiplicity of infection; mRNA, messenger RNA; MTT, 3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; MVD, microvessel density; pfu, plaque forming units; RT-PCR, reverse transcription-polymerase chain reaction; PBS, phosphate buffered saline; EHS, Engelbreth Holm-Swarm

Keywords: adenoviral vectors; antiangiogenesis; gene therapy; pancreatic neoplasms; vasostatin

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Robin Spiller and Alistair Watson
Gut 2006 55: 141. [Extract] [Full Text] [PDF]

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