Systemic co-administration of depsipeptide selectively targets transfection enhancement to specific tissues and cell types.
Depsipeptide, a histone deacetylase (HDAC) inhibitor, kills tumor cells much more effectively than normal cells, and can produce significant antitumor activity in human cancer patients. Depsipeptide also increases the expression of lipoplex-delivered genes in cultured tumor cells, as well as following direct intra-tumoral injection. We now show that co-intravenous (i.v.) injection of depsipeptide with polyethylenimine (PEI):DNA complexes significantly increases the expression of PEI-delivered genes in normal, as well as in tumor-bearing mice. At the tissue level, depsipeptide-mediated enhancement of gene expression was selectively targeted to the lung, liver and spleen. At the cellular level, depsipeptide significantly increased the expression of the i.v., PEI co-delivered wild-type human p53 gene in metastatic breast cancer cells, but not in adjacent normal cells. Thus, the ability of depsipeptide to enhance the expression of systemically delivered genes is selectively targeted at both the tissue and cellular levels, without requiring the use of ligand- or promoter-based approaches. Analyzing HDAC-based targeting of gene expression may identify host genes that control the expression of systemically delivered genes.
Liu
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Y
California Pacific Medical Center Research Institute (CPMCRI), San Francisco, CA, USA.
Liggitt
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D
Fong
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S
Debs
R J
RJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D003124:Colorimetry; D003131:Combined Modality Therapy; D047630:Depsipeptides / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018390:Gene Targeting; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D056572:Histone Deacetylase Inhibitors; D007150:Immunohistochemistry / Q000379:methods; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D013154:Spleen / Q000378:metabolism; D014162:Transfection / Q000379:methods*
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D008156:Luciferases