Abstract
Telomerase activation is considered to be a critical step in cancer progression due to its role in cellular immortalization. The prevalence of telomerase expression in human cancers makes it an attractive candidate for new mechanism-based targets for cancer therapy. The selective killing of cancer cells can be achieved by gene-directed enzyme pro-drug therapy (GDEPT). In this study we have tested the feasibility of using the transcriptional regulatory sequences from the hTERT and hTR genes to regulate expression of the bacterial nitroreductase enzyme in combination with the pro-drug CB1954 in a suicide gene therapy strategy. hTERT and hTR promoter activity was compared in a panel of 10 cell lines and showed a wide distribution in activity; low activity was observed in normal cells and telomerase-negative immortal ALT cell lines, with up to 300-fold higher activity observed in telomerase positive cancer lines. Placing the nitroreductase gene under the control of the telomerase gene promoters sensitized cancer cells in tissue culture to the pro-drug CB1954 and promoter activity was predictive of sensitization to the pro-drug (2–20-fold sensitization), with cell death restricted to lines exhibiting high levels of promoter activity. The in vivo relevance of these data was tested using two xenograft models (C33a and GLC4 cells). Significant tumour reduction was seen with both telomerase promoters and the promoter-specific patterns of sensitization observed in tissue culture were retained in xenograft models. Thus, telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abdul-Ghani R, Ohana P, Matouk I, Ayesh S, Ayesh B, Laster M, Bibi O, Giladi H, Molnar-Kimber K, Sughayer MA, de Groot N, Hochberg A . 2000 Mol. Ther. 2: 539–544
Bailey SM, Hart IR . 1997 Gene Ther. 4: 80–81
Bailey SM, Knox RJ, Hobbs SM, Jenkins TC, Mauger AB, Melton RG, Burke PJ, Connors TA, Hart IR . 1996 Gene Ther. 3: 1143–1150
Gibbs JB . 2000 Science 287: 1969–1973
Greco O, Dachs GU . 2001 J. Cell Physiol. 187: 22–36
Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA, Fang B . 2000 Cancer Res. 60: 5359–5364
Gunes C, Lichtsteiner S, Vasserot AP, Englert C . 2000 Cancer Res. 60: 2116–2121
Harrington KJ, Linardakis E, Vile RG . 2000 Adv. Drug Deliv. Rev. 44: 167–184
Heine B, Hummel M, Demel G, Stein H . 1998 J. Pathol. 185: 139–144
Hiyama E, Hiyama K, Yokoyama T, Shay JW . 2001 Neoplasia 3: 17–26
Hiyama T, Yokozaki H, Kitadai Y, Haruma K, Yasui W, Kajiyama G, Tahara E . 1999 Virchows Arch. 434: 483–487
Hoare SF, Bryce LA, Wisman GB, Burns S, Going JJ, van der Zee AG, Keith WN . 2001 Cancer Res. 61: 27–32
Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, Kyo S, Kondo S . 2000 Hum. Gene Ther. 11: 1397–1406
Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA, Haber DA, Gerald WL . 1998 Nat. Genet. 19: 182–186
Maitra A, Yashima K, Rathi A, Timmons CF, Rogers BB, Shay JW, Gazdar AF . 1999 Cancer 85: 741–749
Majumdar AS, Hughes DE, Lichtsteiner SP, Wang Z, Lebkowski JS, Vasserot AP . 2001 Gene Ther. 8: 568–578
Mistry P, Stewart AJ, Dangerfield W, Okiji S, Liddle C, Bootle D, Plumb JA, Templeton D, Charlton P . 2001 Cancer Res. 61: 749–758
Nettelbeck DM, Jerome V, Muller R . 2000 Trends Genet. 16: 174–181
Nowak R, Chrapusta SJ . 1998 Cancer Journal From Scientific American 4: 148–154
Park TW, Riethdorf S, Riethdorf L, Loning T, Janicke F . 1999 Int. J. Cancer 84: 426–431
Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R . 2000 Cancer Res. 60: 6039–6044
Sarvesvaran J, Going JJ, Milroy R, Kaye SB, Keith WN . 1999 Carcinogenesis 20: 1649–1651
Sharma S, Raymond E, Soda H, Sun D, Hilsenbeck SG, Sharma A, Izbicka E, Windle B, Von Hoff DD . 1997 Ann. Oncol. 8: 1063–1074
Shay JW, Zou Y, Hiyama E, Wright WE . 2001 Hum. Mol. Genet. 10: 677–685
Soder AI, Going JJ, Kaye SB, Keith WN . 1998 Oncogene 16: 979–983
Stanta G, Bonin S, Niccolini B, Raccanelli A, Baralle F . 1999 FEBS Lett. 460: 285–288
Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, Inoue M . 1999 Cancer Res. 59: 551–557
Urquidi V, Tarin D, Goodison S . 1998 Ann. Med. 30: 419–430
Vile RG, Sunassee K, Diaz RM . 1998 Mol. Med. Today 4: 84–92
Weedon SJ, Green NK, McNeish IA, Gilligan MG, Mautner V, Wrighton CJ, Mountain A, Young LS, Kerr DJ, Searle PF . 2000 Int. J. Cancer 86: 848–854
Weng N, Levine BL, June CH, Hodes RJ . 1997 J. Immunol. 158: 3215–3220
White LK, Wright WE, Shay JW . 2001 Trends Biotechnol. 19: 114–120
Wisman GB, De Jong S, Meersma GJ, Helder MN, Hollema H, De Vries EG, Keith WN, Van Der Zee AG . 2000 Hum. Pathol. 31: 1304–1312
Yashima K, Maitra A, Rogers BB, Timmons CF, Rathi A, Pinar H, Wright WE, Shay JW, Gazdar AF . 1998 Cell Growth Diff. 9: 805–813
Yi X, Tesmer VM, Savre-Train I, Shay JW, Wright WE . 1999 Mol. Cell. Biol. 19: 3989–3997
Zhao JQ, Glasspool RM, Hoare SF, Bilsland A, Szatmari II, Keith WN . 2000 Neoplasia 2: 531–539
Zhao JQ, Hoare SF, McFarlane R, Muir S, Parkinson EK, Black DM, Keith WN . 1998 Oncogene 16: 1345–1350
Acknowledgements
This work was supported by the Cancer Research Campaign (UK) and Glasgow University. We would like to thank Dr Caroline Springer for an initial gift of CB1954.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Plumb, J., Bilsland, A., Kakani, R. et al. Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954. Oncogene 20, 7797–7803 (2001). https://doi.org/10.1038/sj.onc.1204954
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204954
Keywords
This article is cited by
-
Research progress of response strategies based on tumor microenvironment in drug delivery systems
Journal of Nanoparticle Research (2021)
-
Telomerase and drug resistance in cancer
Cellular and Molecular Life Sciences (2017)
-
Using intron splicing trick for preferential gene expression in transduced cells: an approach for suicide gene therapy
Cancer Gene Therapy (2016)
-
Telomerase and the endocrine system
Nature Reviews Endocrinology (2011)
-
Nitroreductase-mediated Gonadal Dysgenesis for Infertility Control of Genetically Modified Zebrafish
Marine Biotechnology (2010)