Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma.
Adenoviruses are efficient gene delivery vehicles but have broad native tropism. To this end, finding ways to target this virus specifically to carcinomas has become an important focus of cancer gene therapy. Transductional and transcriptional forms of targeting have been used with promising results in ovarian carcinoma. Therefore, we combined both forms of targeting to investigate the effect on the specificity and efficiency of transgene expression in this disease. We used the tissue-specific SLPI promoter and the ovarian cancer associated targeting adaptor protein, sCARfC6.5. This bispecific protein contains the coxsackie-adenovirus receptor ectodomain and a single-chain antibody specific for c-erbB-2. Viruses containing the SLPI or the ubiquitously expressed CMV promoter, with or without sCARfC6.5, were used for infection of ovarian cancer cell lines, primary ovarian tumor cells, and in an orthotopic model of disseminated ovarian carcinoma. This dual-targeting strategy increased the efficiency and specificity of transgene expression in vitro in reporter and cell-killing assays, and in vivo. By using both the SLPI promoter and sCARfC6.5, transgene expression was increased in ovarian tumors and decreased in normal tissues, including the liver. Thus, we show that combining transcriptional and transductional targeting can increase the efficacy and specificity of adenoviral gene therapy for ovarian carcinoma.
Barker
S D
SD
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Dmitriev
I P
IP
Nettelbeck
D M
DM
Liu
B
B
Rivera
A A
AA
Alvarez
R D
RD
Curiel
D T
DT
Hemminki
A
A
D000230:Adenocarcinoma / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D010051:Ovarian Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D053481:Secretory Leukocyte Peptidase Inhibitor; D014158:Transcription, Genetic; D014161:Transduction, Genetic / Q000379:methods; D014407:Tumor Cells, Cultured
D000906:Antibodies; D008156:Luciferases; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D053481:Secretory Leukocyte Peptidase Inhibitor; C506814:SLPI protein, human; C506815:Slpi protein, mouse