The secretory leukoprotease inhibitor (SLPI) promoter for ovarian cancer gene therapy.
BACKGROUND
Adenoviruses allow efficient transduction of dividing and non-dividing cells and their safety for the treatment of cancer has been established in clinical trials. However, one disadvantage is their promiscuous tropism. In this regard, tissue-specific promoters (TSPs) could be useful for directing transgene expression to target tissues and for reducing adverse effects in non-target tissues. We hypothesize that selective adenovirus-mediated transgene expression could be achieved through the use of the secretory leukoprotease inhibitor (SLPI) promoter in the context of ovarian cancer.


METHODS
Adenoviruses containing the SLPI promoter driving reporter and suicide gene expression were created and tested in ovarian cancer cell lines and primary tumor cells isolated from patients. To evaluate the in vivo activation of the SLPI promoter in comparison to a ubiquitous promoter, intraperitoneal delivery was performed in tumor-bearing mice, followed by analysis of survival or gene expression in normal organs and tumor.


RESULTS
The SLPI promoter retained its fidelity in an adenoviral context and was activated in both cell lines and primary cancer cells. The SLPI promoter was induced to a high degree in ovarian cancer cells while showing significantly reduced activity in normal tissues. The therapeutic efficacy of SLPI promoter-controlled gene expression was similar to the ubiquitous promoter in vitro and in an orthotopic murine model of peritoneally disseminated ovarian cancer, with higher activity than controls.


CONCLUSIONS
The SLPI promoter is a potentially useful TSP for ovarian cancer and facilitates further development of targeting strategies for improved gene therapy of ovarian carcinomas.
Barker
Shannon D
SD
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Coolidge
Candace J
CJ
Kanerva
Anna
A
Hakkarainen
Tanja
T
Yamamoto
Masato
M
Liu
Bin
B
Rivera
Angel A
AA
Bhoola
Snehal M
SM
Barnes
Mack N
MN
Alvarez
Ronald D
RD
Curiel
David T
DT
Hemminki
Akseli
A
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013937:Thymidine Kinase