Use of H19 regulatory sequences for targeted gene therapy in cancer.
We present a tumor gene therapy approach based on the use of regulatory sequences of the H19 gene that are differentially expressed between normal and cancer cells. We constructed expression vectors carrying the gene for the A fragment of diphtheria toxin (DT-A) or herpes simplex virus thymidine kinase (HSV-tk), under the control of a 814 bp 5'-flanking region of the H19 gene. The cell killing activity of these constructs was in accordance with the relative activity of the H19 regulatory sequences in the transfected cells. We evaluated the therapeutic potential of the gene expression constructs driven by H19 regulatory sequences in an animal model of bladder cancer induced by subcutaneous injection of syngeneic bladder tumor cell lines. Intratumoral injection of these constructs caused a significant suppression of subcutaneous tumor growth, with no obvious toxicity toward the host.
Ohana
Patricia
P
Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel. pohana@mail.ls.huji.ac.il
Bibi
Osaat
O
Matouk
Imad
I
Levy
Carol
C
Birman
Tatiana
T
Ariel
Ilana
I
Schneider
Tamar
T
Ayesh
Suhail
S
Giladi
Hilla
H
Laster
Morris
M
de Groot
Nathan
N
Hochberg
Abraham
A
D000818:Animals; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D010446:Peptide Fragments / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D013937:Thymidine Kinase / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000628:therapy*
D004167:Diphtheria Toxin; C094335:H19 long non-coding RNA; D010446:Peptide Fragments; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C029795:diphtheria toxin fragment A; D008156:Luciferases; D013937:Thymidine Kinase; D015774:Ganciclovir