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Bystander cell killing spreading from endothelial to tumor cells in a three-dimensional multicellular nodule model after Escherichia coli nitroreductase gene delivery.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2003 Nov 28; Vol. 311 (4), pp. 822-8. - Publication Year :
- 2003
-
Abstract
- Tumor cells are elusive targets for standard anticancer chemotherapy due to their heterogeneity and genetic instability. On the other hand, proliferating host endothelial cells (ECs) are genetically stable and have a low mutational rate. Thus, antiangiogenic therapy directed against tumor's ECs should, in principle, improve the efficacy of antitumor therapy by inducing little or no drug resistance. Here we present a gene-directed enzyme prodrug therapy (GDEPT) strategy for targeting the tumor vasculature, using the Escherichia coli nitroreductase (ntr) gene delivery associated with the treatment with the prodrug CB1954. In a first time we demonstrated the ability of the ntr/CB1954 system to induce an apoptotic-mediated cell death on monolayer cultures of human umbilical vein ECs (HUV-EC-C). Then, when ntr-transfected HUV-EC-C cells (HUV-EC-C/ntr(+)) were associated in a three-dimensional (3-D) multicellular nodule model with untransfected B16-F10 murine melanoma cell line, we observed a CB1954-mediated bystander cell killing effect from endothelial to neighboring melanoma cells. To our knowledge, this is the first report indicating that GDEPT-based antiangiogenic targeting may be an effective approach for cancer treatment relied on the spreading of the bystander effect from endothelial to tumor cells.
- Subjects :
- Animals
Humans
Mice
3T3 Cells
Antineoplastic Agents pharmacology
Apoptosis drug effects
Apoptosis genetics
Cell Line
Cell Line, Tumor
Cell Survival drug effects
Cell Survival genetics
Coculture Techniques methods
Dose-Response Relationship, Drug
Escherichia coli enzymology
Escherichia coli genetics
Prodrugs administration & dosage
Umbilical Veins drug effects
Umbilical Veins metabolism
Aziridines administration & dosage
Bystander Effect genetics
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Genetic Therapy methods
Melanoma genetics
Melanoma metabolism
Melanoma pathology
Nitroreductases genetics
Nitroreductases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-291X
- Volume :
- 311
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 14623255
- Full Text :
- https://doi.org/10.1016/j.bbrc.2003.10.068