Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences.
BACKGROUND
Ovarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer), while existing at a nearly undetectable level in the surrounding normal tissue.


METHODS
H19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH) using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer.


RESULTS
H19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth.


CONCLUSIONS
These observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.
Mizrahi
Aya
A
The Department of Biological Chemistry, Institute of Life Sciences, Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel. amizrah25@gmail.com
Czerniak
Abraham
A
Levy
Tally
T
Amiur
Smadar
S
Gallula
Jennifer
J
Matouk
Imad
I
Abu-lail
Rasha
R
Sorin
Vladimir
V
Birman
Tatiana
T
de Groot
Nathan
N
Hochberg
Abraham
A
Ohana
Patricia
P
D000818:Animals; D001201:Ascites / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
D004167:Diphtheria Toxin; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated