Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’)

Oncogene volume 24, pages 3130–3140 (2005)Cite this article

Abstract

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus (OBP-301, ‘Telomelysin’), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES, could replicate in cancer cells, and causes selective lysis of cancer cells. We further constructed OBP-405 (‘Telomelysin-RGD’) that contains an RGD motif in the HI loop of the fiber knob. We examined whether OBP-405 could be effective in overcoming the limitations of OBP-301, specifically their inefficient infection into cells lacking the primary receptor, the coxsackievirus and adenovirus receptor (CAR). By flow cytometric analysis, H1299 (lung) and SW620 (colorectal) tumor cells showed high levels of CAR expression, whereas LN444 (glioblastoma), LNZ308 (glioblastoma), and H1299-R5 (lung) tumor cells were negative for CAR expression. A quantitative real-time PCR analysis demonstrated that fiber-modified OBP-405 infected more efficiently than OBP-301, although the intracellular replication rate of both viruses was consistent. The comparative antitumor effect of fiber-modified OBP-405 and unmodified OBP-301 for human cancer cells was evaluated in vitro by XTT assay as well as in vivo by using athymic mice carrying xenografts. OBP-405 had a profound oncolytic effect on human cancer cell lines compared to OBP-301, in particular on cells with low CAR expression. Intratumoral injection of 107 plaque-forming units of OBP-405 into CAR-negative H1299-R5 lung tumor xenografts in nu/nu mice resulted in a significant inhibition of tumor growth and long-term survival in all treated mice. Moreover, selective replication of OBP-405 in the distant, uninjected H1299-R5 tumors was demonstrated. Our results suggest that fiber-modified replication-competent adenovirus OBP-405 exhibits a broad target range by increasing infection efficiency, an outcome that has important implications for the treatment of human cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

hTERT:

human telomerase reverse transcriptase

IRES:

internal ribosome entry site

CAR:

Coxsackie-adenovirus receptor

NHLF:

normal human lung fibroblasts

MOI:

multiplicity of infection

PFU:

plaque-forming units

References

  • Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL and Finberg RW . (1997). Science, 275, 1320–1323.

  • Collins K and Mitchell JR . (2002). Oncogene, 21, 564–579.

  • Davydova J, Le LP, Gavrikova T, Wang M, Krasnykh V and Yamamoto M . (2004). Cancer Res., 64, 4319–4327.

  • DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M, Hamper U, DeJong R, Detorie N, Rodriguez R, Haulk T, DeMarzo AM, Piantadosi S, Yu DC, Chen Y, Henderson DR, Carducci MA, Nelson WG and Simons JW . (2001). Cancer Res., 61, 7464–7472.

  • Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G, Belousova N and Curiel DT . (1998). J. Virol., 72, 9706–9713.

  • Fang B and Roth JA . (2003). Curr. Opin. Mol. Ther., 5, 475–482.

  • Fechner H, Wang X, Wang H, Jansen A, Pauschinger M, Scherubl H, Bergelson JM, Schultheiss HP and Poller W . (2000). Gene Ther., 7, 1954–1968.

  • Ginsberg HS, Moldawer LL, Sehgal PB, Redington M, Kilian PL, Chanock RM and Prince GA . (1991). Proc. Natl. Acad. Sci. USA, 88, 1651–1655.

  • Greider CW and Blackburn EH . (1985). Cell, 43, 405–413.

  • Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA and Fang B . (2000). Cancer Res., 60, 5359–5364.

  • Gu J, Zhang L, Huang X, Lin T, Yin M, Xu K, Ji L, Roth JA and Fang B . (2002). Oncogene, 21, 4757–4764.

  • Hemminki A, Kanerva A, Liu B, Wang M, Alvarez RD, Siegal GP and Curiel DT . (2003). Cancer Res., 63, 847–853.

  • Huard J, Lochmuller H, Acsadi G, Jani A, Massie B and Karpati G . (1995). Gene Ther., 2, 107–115.

  • Kanegae Y, Makimura M and Saito I . (1994). Jpn. J. Med. Sci. Biol., 47, 157–166.

  • Kawashima T, Kagawa S, Kobayashi N, Shirakiya Y, Umeoka T, Teraishi F, Taki M, Kyo S, Tanaka N and Fujiwara T . (2004). Clin. Cancer Res., 10, 285–292.

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL and Shay JW . (1994). Science, 266, 2011–2015.

  • Kirn D, Martuza RL and Zwiebel J . (2001). Nat. Med., 7, 781–787.

  • Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, Kyo S and Kondo S . (2000). Hum. Gene Ther., 11, 1397–1406.

  • Kohn EC, Lu Y, Wang H, Yu Q, Yu S, Hall H, Smith DL, Meric-Bernstam F, Hortobagyi GN and Mills GB . (2004) 31, 39–53.

  • Komata T, Kondo Y, Kanzawa T, Hirohata S, Koga S, Sumiyoshi H, Srinivasula SM, Barna BP, Germano IM, Takakura M, Inoue M, Alnemri ES, Shay JW, Kyo S and Kondo S . (2001). Cancer Res., 61, 5796–5802.

  • Krasnykh V, Dmitriev I, Mikheeva G, Miller CR, Belousova N and Curiel DT . (1998). J. Virol., 72, 1844–1852.

  • Lamfers ML, Grill J, Dirven CM, Van Beusechem VW, Geoerger B, Van Den Berg J, Alemany R, Fueyo J, Curiel DT, Vassal G, Pinedo HM, Vandertop WP and Gerritsen WR . (2002). Cancer Res., 62, 5736–5742.

  • Li Y, Pong RC, Bergelson JM, Hall MC, Sagalowsky AI, Tseng CP, Wang Z and Hsieh JT . (1999). Cancer Res., 59, 325–330.

  • Maizel JVJ, White DO and Scharff MD . (1968). Virology, 36, 115–125.

  • McCormick F . (2001). Nat. Rev. Cancer, 1, 130–141.

  • Miller CR, Buchsbaum DJ, Reynolds PN, Douglas JT, Gillespie GY, Mayo MS, Raben D and Curiel DT . (1998). Cancer Res., 58, 5738–5748.

  • Mizuguchi H, Koizumi N, Hosono T, Utoguchi N, Watanabe Y, Kay MA and Hayakawa T . (2001). Gene Ther., 8, 730–735.

  • Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB and Cech TR . (1997). Science, 277, 955–959.

  • Prince GA, Porter DD, Jenson AB, Horswood RL, Chanock RM and Ginsberg HS . (1993). J. Virol., 67, 101–111.

  • Shay JW and Wright WE . (1996). Curr. Opin. Oncol., 8, 66–71.

  • Tango Y, Taki M, Shirakiya Y, Ohtani S, Tokunaga N, Tsunemitsu Y, Kagawa S, Tani T, Tanaka N and Fujiwara T . (2004). Cancer Sci., 95, 459–643.

  • Tomko RP, Xu R and Philipson L . (1997). Proc. Natl. Acad. Sci. USA, 94, 3352–3356.

  • Umeoka T, Kawashima T, Kagawa S, Teraishi F, Taki M, Nishizaki M, Kyo S, Nagai K, Urata Y, Tanaka N and Fujiwara T . (2004). Cancer Res., 64, 6259–6265.

  • Wickham TJ, Mathias P, Cheresh DA and Nemerow GR . (1993). Cell, 73, 309–319.

  • Wickham TJ, Tzeng E, Shears II LL, Roelvink PW, Li Y, Lee GM, Brough DE, Lizonova A and Kovesdi I . (1997). J. Virol., 71, 8221–8229.

  • Wood M, Perrotte P, Onishi E, Harper ME, Dinney C, Pagliaro L and Wilson DR . (1999). Cancer Gene Ther., 6, 367–372.

Download references

Acknowledgements

We thank Yoshiko Shirakiya, Nobue Mukai, and Yuri Hashimoto (Oncolys BioPharma, Inc.) for their excellent technical support. This work was supported in part by grants from the Ministry of Education, Science and Culture, Japan; and by grants from the Ministry of Health and Welfare, Japan.

Author information

Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, 700-8558, Japan

    Masaki Taki, Shunsuke Kagawa, Masahiko Nishizaki, Noriaki Tanaka & Toshiyoshi Fujiwara

  2. Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, 700-8558, Japan

    Shunsuke Kagawa & Toshiyoshi Fujiwara

  3. Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo, 158-8501, Japan

    Hiroyuki Mizuguchi & Takao Hayakawa

  4. Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, Kanazawa, 920-8641, Japan

    Satoru Kyo

  5. Oncolys BioPharma, Inc., Tokyo, 106-0031, Japan

    Katsuyuki Nagai & Yasuo Urata

Authors
  1. Masaki Taki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shunsuke Kagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masahiko Nishizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyuki Mizuguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takao Hayakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoru Kyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katsuyuki Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasuo Urata
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Noriaki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toshiyoshi Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiyoshi Fujiwara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taki, M., Kagawa, S., Nishizaki, M. et al. Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’). Oncogene 24, 3130–3140 (2005). https://doi.org/10.1038/sj.onc.1208460

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208460

Keywords

This article is cited by

Search

Advanced search

Quick links