Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors

Eiji Kikuchi, Silvia Menendez, Choichiro Ozu, Makoto Ohori, Carlos Cordon-Cardo, Christopher R. Logg, Noriyuki Kasahara, Bernard H. Bochner

Research output: Contribution to journalArticle

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Abstract

Purpose: In an attempt to improve viral delivery of potentially therapeutic genes via an intravesical route, we have recently developed murine leukemia virus-based replication-competent retrovirus (RCR) vectors. Experimental Design: We evaluated the transduction efficiency of intravesically administered RCR vectors to bladder tumor using orthotopic animal models to determine their potential as delivery vectors for bladder cancer. Results: The RCR vector containing green fluorescent protein (GFP) marker gene achieved efficient in vitro transmission of the GFP transgene. Murine bladder tumor-2 mouse bladder tumors exposed to intravesically administered RCR vectors exhibited 0%, 9.2 ± 2.9%, and 30.0 ± 6.2% of GFP expression at 9, 18, and 27 days after exposure in the orthotopic model, respectively. Orthotopic KU-19-19 human bladder tumors exposed to intravesically administered RCR vectors exhibited 3%, 85 ± 1.0%, and 100% of GFP expression at 7, 21, and 35 days after exposure, respectively. GFP staining was observed only in the tumor cells in the bladder. No detectable PCR products of GFP gene could be observed in distant organs. Treatment with RCR vectors containing yeast cytosine deaminase (CD) gene plus 5-fluorocytosine (5-FC) dramatically inhibited the growth of preestablished murine bladder tumor-2 tumors. A single course of 5-FC treatment resulted in a 50% animal survival in mice exposed to RCR-CD compared with a 0% survival in all controls over a 70-day follow-up period. Conclusions: Intravesically administered RCR vectors can efficiently deliver genes to orthotopic bladder tumor without viral spread in distant organs. RCR-CD/5-FC suicide gene therapy promises to be a novel and potentially therapeutic modality for bladder cancer.

Original languageEnglish
Pages (from-to)4511-4518
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number15
DOIs
Publication statusPublished - 2007 Aug 1
Externally publishedYes

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Retroviridae
Urinary Bladder Neoplasms
Green Fluorescent Proteins
Cytosine Deaminase
Genes
Flucytosine
Murine Leukemia Viruses
Therapeutics
Virus Replication
Transgenes
Genetic Therapy
Suicide
Neoplasms
Urinary Bladder
Research Design
Animal Models
Yeasts
Staining and Labeling
Polymerase Chain Reaction
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kikuchi, E., Menendez, S., Ozu, C., Ohori, M., Cordon-Cardo, C., Logg, C. R., ... Bochner, B. H. (2007). Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors. Clinical Cancer Research, 13(15), 4511-4518. https://doi.org/10.1158/1078-0432.CCR-07-0151

Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors. / Kikuchi, Eiji; Menendez, Silvia; Ozu, Choichiro; Ohori, Makoto; Cordon-Cardo, Carlos; Logg, Christopher R.; Kasahara, Noriyuki; Bochner, Bernard H.

In: Clinical Cancer Research, Vol. 13, No. 15, 01.08.2007, p. 4511-4518.

Research output: Contribution to journalArticle

Kikuchi, E, Menendez, S, Ozu, C, Ohori, M, Cordon-Cardo, C, Logg, CR, Kasahara, N & Bochner, BH 2007, 'Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors', Clinical Cancer Research, vol. 13, no. 15, pp. 4511-4518. https://doi.org/10.1158/1078-0432.CCR-07-0151
Kikuchi, Eiji ; Menendez, Silvia ; Ozu, Choichiro ; Ohori, Makoto ; Cordon-Cardo, Carlos ; Logg, Christopher R. ; Kasahara, Noriyuki ; Bochner, Bernard H. / Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 15. pp. 4511-4518.
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abstract = "Purpose: In an attempt to improve viral delivery of potentially therapeutic genes via an intravesical route, we have recently developed murine leukemia virus-based replication-competent retrovirus (RCR) vectors. Experimental Design: We evaluated the transduction efficiency of intravesically administered RCR vectors to bladder tumor using orthotopic animal models to determine their potential as delivery vectors for bladder cancer. Results: The RCR vector containing green fluorescent protein (GFP) marker gene achieved efficient in vitro transmission of the GFP transgene. Murine bladder tumor-2 mouse bladder tumors exposed to intravesically administered RCR vectors exhibited 0{\%}, 9.2 ± 2.9{\%}, and 30.0 ± 6.2{\%} of GFP expression at 9, 18, and 27 days after exposure in the orthotopic model, respectively. Orthotopic KU-19-19 human bladder tumors exposed to intravesically administered RCR vectors exhibited 3{\%}, 85 ± 1.0{\%}, and 100{\%} of GFP expression at 7, 21, and 35 days after exposure, respectively. GFP staining was observed only in the tumor cells in the bladder. No detectable PCR products of GFP gene could be observed in distant organs. Treatment with RCR vectors containing yeast cytosine deaminase (CD) gene plus 5-fluorocytosine (5-FC) dramatically inhibited the growth of preestablished murine bladder tumor-2 tumors. A single course of 5-FC treatment resulted in a 50{\%} animal survival in mice exposed to RCR-CD compared with a 0{\%} survival in all controls over a 70-day follow-up period. Conclusions: Intravesically administered RCR vectors can efficiently deliver genes to orthotopic bladder tumor without viral spread in distant organs. RCR-CD/5-FC suicide gene therapy promises to be a novel and potentially therapeutic modality for bladder cancer.",
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