Microencapsulated iNOS-expressing cells cause tumor suppression in mice.
Macrophages can kill tumor cells by releasing high levels of nitric oxide (NO) and related reactive nitrogen species such as nitroxyl and peroxynitrite, after up-regulation of expression of the inducible nitric oxide synthase gene (iNOS). In this paper we describe two novel human cell lines that are capable of expressing high levels of iNOS under the control of analogues of either the insect hormone ecdysone or tetracycline. We have entrapped these iNOS-expressing cells within a semipermeable alginate-poly-L-lysine membrane as a means of delivery to tumor sites in a nude mouse model. These encapsulated cells can be induced to generate sustainable high concentrations NO and reactive nitrogen species at tumor sites after treatment either with ponasterone A or muristerone A or with doxycycline. Delivery of these iNOS-expressing cells to tumors formed from human ovarian cancer SKOV-3 cells results in 100% killing, whereas treatment of tumors formed from human colon cancer DLD-1 cells results in 54% killing. We show that in these iNOS-expressing cells, tumor killing is associated with concomitant up-regulation of the Fas/FasL proteins.
Xu
Weiming
W
The Wolfson Institute for Biomedical Research, UCL, London, WC1E 6BT, UK.
Liu
Lizhi
L
Charles
Ian G
IG
D000464:Alginates; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002460:Cell Line; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011107:Polylysine / Q000031:analogs & derivatives*; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000464:Alginates; D000900:Anti-Bacterial Agents; C051546:alginate-polylysine-alginate; D011107:Polylysine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013752:Tetracycline; D004318:Doxycycline