HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jnumed.107.042226v1 48/9/1519    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM 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 Google Scholar Google Scholar Articles by Mairs, R. J. Articles by Boyd, M. Search for Related Content PubMed PubMed Citation Articles by Mairs, R. J. Articles by Boyd, M.

A Transfectant Mosaic Xenograft Model for Evaluation of Targeted Radiotherapy in Combination with Gene Therapy In Vivo

¹ Targeted Therapy Group, Division of Cancer Science and Molecular Pathology, Glasgow University, Cancer Research United Kingdom Beatson Laboratories, Glasgow, United Kingdom; ² Department of Child Health, Yorkhill Hospital, Glasgow, United Kingdom; and ³ Targeted Therapy Group, Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research United Kingdom Beatson Laboratories, Glasgow, United Kingdom

Correspondence: For correspondence or reprints contact: Marie Boyd, PhD, Targeted Therapy Group, Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research United Kingdom Beatson Laboratories, Glasgow G61 1BD, U.K. E-mail: m.boyd{at}beatson.gla.ac.uk

For gene therapy to be efficacious in the treatment of cancer, therapeutic transgenes must be limited in their expression to tumor cells and must be expressed at sufficiently high transcriptional levels. Moreover, the inadequacy of gene delivery must be overcome by induction of toxicity to neighboring nontargeted cells. Combining targeted radionuclide therapy with gene therapy using human telomerase promoters has shown promise in these respects, and the efficacy of this scheme has been assessed in vitro using transfectant mosaic tumor spheroids. To enable the evaluation of targeted radiotherapy combined with gene transfer in vivo, we have developed a transfectant mosaic xenograft (TMX) model. Methods: Human telomerase promoters were used to drive expression of the noradrenaline transporter (NAT) transgene in 2 human cell lines (UVW and EJ138). Promoter activity was assessed in xenografts in nude mice by determination of the uptake of the radiopharmaceutical ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) and by measurement of tumor growth. The efficacy of ¹³¹I-MIBG treatment was also assessed in TMXs to determine the delay in growth of tumors composed of various proportions of NAT-expressing cells—a likely clinical scenario after gene delivery in vivo. Results: In terms of induction of the capacity for active uptake of ¹³¹I-MIBG and the resultant inhibition of tumor growth in vivo, both telomerase promoters (hTR and hTERT) were similar in potency to the CMV (cytomegalovirus) promoter as controlling elements for the expression of the NAT transgene. In TMXs derived from UVW and EJ138 cells, ¹³¹I-MIBG uptake was proportional to NAT gene expression (r_s = 0.910, P < 0.001 for UVW; r_s = 0.971, P < 0.001 for EJ138). Inhibition of the growth of these tumors correlated with the fraction of NAT-transfected cells (r_s = 0.910, P < 0.001 for UVW; r_s = 0.971, P < 0.001 for EJ138), and substantial tumor growth delay was observed when 5% of the xenograft was composed of NAT-positive cells. Conclusion: TMXs constitute a suitable model to measure the efficacy of cancer gene therapy strategies when <100% of the tumor mass can be targeted to express the therapeutic transgene.

Key Words: targeted radionuclide therapy • cancer gene therapy • in vivo model • bystander effects

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

Related articles in JNM:

This Month in JNM

JNM 2007 48: 11A-12A. [Full Text]