This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dufès, C. Articles by Schätzlein, A. G. Search for Related Content PubMed PubMed Citation Articles by Dufès, C. Articles by Schätzlein, A. G.

Synthetic Anticancer Gene Medicine Exploits Intrinsic Antitumor Activity of Cationic Vector to Cure Established Tumors

¹ Cancer Research UK Centre for Oncology and Applied Pharmacology, Beatson Laboratories, University of Glasgow, and ² Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, United Kingdom

Requests for reprints: Andreas G. Schätzlein, Cancer Research UK Centre for Oncology and Applied Pharmacology, Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, United Kingdom. Phone: 44-141-330-4354; E-mail: A.Schatzlein{at}beatson.gla.ac.uk.

The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor (TNF) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNF expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNF when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.

This article has been cited by other articles:

				E Chisholm, U Bapat, C Chisholm, G Alusi, and G Vassaux Gene therapy in head and neck cancer: a review Postgrad. Med. J., December 1, 2007; 83(986): 731 - 737. [Abstract] [Full Text] [PDF]

				A. E. Bilsland, A. Merron, G. Vassaux, and W. N. Keith Modulation of Telomerase Promoter Tumor Selectivity in the Context of Oncolytic Adenoviruses Cancer Res., February 1, 2007; 67(3): 1299 - 1307. [Abstract] [Full Text] [PDF]

				C. C. Lee, E. R. Gillies, M. E. Fox, S. J. Guillaudeu, J. M. J. Frechet, E. E. Dy, and F. C. Szoka A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas PNAS, November 7, 2006; 103(45): 16649 - 16654. [Abstract] [Full Text] [PDF]