Abstract
Replication-competent retrovirus (RCR) vectors have been shown to achieve significantly enhanced tumor transduction efficiency and therapeutic efficacy in various cancer models. In the present study, we investigated RCR vector-mediated prodrug activator gene therapy for the treatment of malignant mesothelioma, a highly aggressive tumor with poor prognosis. RCR-GFP vector expressing the green fluorescent protein marker gene successfully infected and efficiently replicated in human malignant mesothelioma cell lines, as compared with non-malignant mesothelial cells in vitro. In mice with pre-established subcutaneous tumor xenografts, RCR-GFP vector showed robust spread throughout entire tumor masses after intratumoral administration. Next, RCR-cytosine deaminase (RCR-CD), expressing the yeast CD prodrug activator gene, showed efficient transmission of the prodrug activator gene associated with replicative spread of the virus, resulting in efficient killing of malignant mesothelioma cells in a prodrug 5-fluorocytosine (5FC)-dose dependent manner in vitro. After a single intratumoral injection of RCR-CD followed by intraperitoneal administration of 5FC, RCR vector-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. These data indicate the potential utility of RCR vector-mediated prodrug activator gene therapy in the treatment of malignant mesothelioma.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 571-578 |
| Number of pages | 8 |
| Journal | Cancer Gene Therapy |
| Volume | 18 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2011 |
| Externally published | Yes |
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Keywords
- malignant mesothelioma
- molecular imaging
- prodrug activator gene therapy
- replication-competent retrovirus vector
ASJC Scopus subject areas
- Cancer Research
- Molecular Medicine
- Molecular Biology
Cite this
Replication-competent retrovirus vector-mediated prodrug activator gene therapy in experimental models of human malignant mesothelioma. / Kawasaki, Y.; Tamamoto, A.; Takagi-Kimura, M.; Maeyama, Y.; Yamaoka, N.; Terada, N.; Okamura, H.; Kasahara, Noriyuki; Kubo, S.
In: Cancer Gene Therapy, Vol. 18, No. 8, 08.2011, p. 571-578.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Replication-competent retrovirus vector-mediated prodrug activator gene therapy in experimental models of human malignant mesothelioma
AU - Kawasaki, Y.
AU - Tamamoto, A.
AU - Takagi-Kimura, M.
AU - Maeyama, Y.
AU - Yamaoka, N.
AU - Terada, N.
AU - Okamura, H.
AU - Kasahara, Noriyuki
AU - Kubo, S.
PY - 2011/8
Y1 - 2011/8
N2 - Replication-competent retrovirus (RCR) vectors have been shown to achieve significantly enhanced tumor transduction efficiency and therapeutic efficacy in various cancer models. In the present study, we investigated RCR vector-mediated prodrug activator gene therapy for the treatment of malignant mesothelioma, a highly aggressive tumor with poor prognosis. RCR-GFP vector expressing the green fluorescent protein marker gene successfully infected and efficiently replicated in human malignant mesothelioma cell lines, as compared with non-malignant mesothelial cells in vitro. In mice with pre-established subcutaneous tumor xenografts, RCR-GFP vector showed robust spread throughout entire tumor masses after intratumoral administration. Next, RCR-cytosine deaminase (RCR-CD), expressing the yeast CD prodrug activator gene, showed efficient transmission of the prodrug activator gene associated with replicative spread of the virus, resulting in efficient killing of malignant mesothelioma cells in a prodrug 5-fluorocytosine (5FC)-dose dependent manner in vitro. After a single intratumoral injection of RCR-CD followed by intraperitoneal administration of 5FC, RCR vector-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. These data indicate the potential utility of RCR vector-mediated prodrug activator gene therapy in the treatment of malignant mesothelioma.
AB - Replication-competent retrovirus (RCR) vectors have been shown to achieve significantly enhanced tumor transduction efficiency and therapeutic efficacy in various cancer models. In the present study, we investigated RCR vector-mediated prodrug activator gene therapy for the treatment of malignant mesothelioma, a highly aggressive tumor with poor prognosis. RCR-GFP vector expressing the green fluorescent protein marker gene successfully infected and efficiently replicated in human malignant mesothelioma cell lines, as compared with non-malignant mesothelial cells in vitro. In mice with pre-established subcutaneous tumor xenografts, RCR-GFP vector showed robust spread throughout entire tumor masses after intratumoral administration. Next, RCR-cytosine deaminase (RCR-CD), expressing the yeast CD prodrug activator gene, showed efficient transmission of the prodrug activator gene associated with replicative spread of the virus, resulting in efficient killing of malignant mesothelioma cells in a prodrug 5-fluorocytosine (5FC)-dose dependent manner in vitro. After a single intratumoral injection of RCR-CD followed by intraperitoneal administration of 5FC, RCR vector-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. These data indicate the potential utility of RCR vector-mediated prodrug activator gene therapy in the treatment of malignant mesothelioma.
KW - malignant mesothelioma
KW - molecular imaging
KW - prodrug activator gene therapy
KW - replication-competent retrovirus vector
UR - http://www.scopus.com/inward/record.url?scp=79960556047&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960556047&partnerID=8YFLogxK
U2 - 10.1038/cgt.2011.25
DO - 10.1038/cgt.2011.25
M3 - Article
C2 - 21660062
AN - SCOPUS:79960556047
VL - 18
SP - 571
EP - 578
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
SN - 0929-1903
IS - 8
ER -