In vivo therapy of hepatocellular carcinoma with a tumor-specific adenoviral vector expressing interleukin-2.
A recombinant adenovirus (AdVAFP1-IL2) containing the murine alpha-fetoprotein (AFP) promoter was constructed to direct hepatocellular carcinoma (HCC)-specific expression of the human interleukin-2 (IL-2) gene. In vitro testing of AdVAFP1-IL2 showed HCC-specific IL-2 gene expression three to four orders of magnitude higher in AFP-producing HCC lines compared to non-AFP producing non-HCC lines. The in vivo efficacy and tumor specificity of AdVAFP1-IL2 was evaluated compared to AdVCMV-IL2 (in which the IL-2 gene is driven by the strong constitutive cytomegalovirus promoter) in the treatment of established human HCC (Hep 3B/Hep G2) xenografts growing in CB-17/SCID mice. Intratumoral injection of AdV resulted in growth retardation and regression in a majority of established hepatomas, but with a much wider therapeutic index and less systemic toxicity using the AFP vector. This study illustrates the superiority of using transcriptionally targeted recombinant AdV vectors in cytokine-based gene therapy.
Bui
L A
LA
Division of Surgical Oncology, UCLA School of Medicine, Los Angeles, CA 90095-1782, USA.
Butterfield
L H
LH
Kim
J Y
JY
Ribas
A
A
Seu
P
P
Lau
R
R
Glaspy
J A
JA
McBride
W H
WH
Economou
J S
JS
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000628:therapy*; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000235:genetics
D007376:Interleukin-2; D000509:alpha-Fetoproteins