Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB-2 intracellular single-chain antibody for ovarian cancer gene therapy.
We have previously shown that adenoviral-mediated delivery of an anti-erbB-2 intracellular single-chain antibody (sFv) causes specific cytotoxicy in erbB-2-overexpressing ovarian carcinoma cells. Furthermore, intraperitoneal delivery of the anti-erbB-2 sFv enhances survival and reduces tumor burden in a xenograft model of human ovarian carcinoma in SCID mice. These findings have led to an RAC-approved Phase I clinical trial for patients with ovarian cancer. In this report, we show that expression of the anti-erbB-2 sFv could be readily detected in target tumor cells by in situ hybridization methodology. PCR analysis of DNA extracted from various murine tissues demonstrated that the anti-erbB-2 sFv remained localized to the peritoneum. Delivery of the sFv to the non-erbB-2-overexpressing REN mesothelial and Hep G2 hepatocellular carcinoma cell lines was not deleterious to either one, affirming the tumor specificity of this gene therapy strategy. In addition, histopathological analysis of various tissues showed that adenoviral-mediated delivery of the anti-erbB-2 sFv to immunocompetent mice with either primary exposure or previous vector challenge at different doses produced no abnormal changes when compared to untreated animals. These findings suggest that adenoviral-mediated delivery of the anti-erbB-2 sFv in a human context can be effectively assayed, is potentially free of vector-associated toxicity, and retains biologic utility based on tumor specificity.
Deshane
J
J
Gene Therapy Program, University of Alabama at Birmingham, 35294, USA.
Siegal
G P
GP
Wang
M
M
Wright
M
M
Bucy
R P
RP
Alvarez
R D
RD
Curiel
D T
DT
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000912:Antibodies, Neoplasm / Q000235:genetics*; D005260:Female; D018734:Genes, erbB-2 / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D010051:Ovarian Neoplasms / Q000628:therapy*; D010537:Peritoneum
D000912:Antibodies, Neoplasm