title: Bystander cell killing spreading from endothelial to tumor cells in a three-dimensional multicellular nodule model after Escherichia coli nitroreductase gene delivery.
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.
authors: UPRES-2360 Ciblage et imagerie fonctionnels de la progression tumorale, Université de Médecine Paris-XIII, Bobigny, France.
authors: Malika
authors: M
authors: Benouchan
authors: Filipe
authors: F
authors: Do Nascimento
authors: Malika
authors: M
authors: Sebbah-Louriki
authors: Jean Loup
authors: JL
authors: Salzmann
authors: Michel
authors: M
authors: Crépin
authors: Gérard Y
authors: GY
authors: Perret
authors: Bruno M
authors: BM
authors: Colombo
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D016475:3T3 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001388:Aziridines / Q000008:administration & dosage; D024201:Bystander Effect / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018920:Coculture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009601:Nitroreductases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D009601:Nitroreductases; D011355:Prodrugs; C100099:tretazicar