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Combined adenovirus-mediated nitroreductase gene delivery and CB1954 treatment: a well-tolerated therapy for established solid tumors.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2001 Feb; Vol. 3 (2), pp. 233-40. - Publication Year :
- 2001
-
Abstract
- Gene-directed enzyme prodrug therapy (GDEPT) is a refinement of cancer chemotherapy that generates a potent cell-killing drug specifically in tumor cells by enzymatic activation of an inert prodrug. We describe in vivo studies that evaluate the efficacy and safety of intratumoral (i.t.) injection of an adenovirus vector (CTL102) expressing Escherichia coli nitroreductase (NTR) combined with systemic prodrug (CB1954) treatment. A single i.t. injection of CTL102 (7.5 x 10(9) to -2 x 10(10) particles) followed by CB1954 treatment produced clear anti-tumor effects in subcutaneous (s.c.) xenograft models of four cancers that are likely candidates for GDEPT (i.e., primary liver, head and neck, colorectal and prostate). Virus dose-response studies (s.c. liver model) revealed a steep increase and subsequent rapid plateauing of both NTR gene delivery and anti-tumor efficacy. Evidence of minor virus spread (toxicity) was observed in a s.c. head and neck xenograft model. This was eliminated by passive immunization with neutralizing anti-Ad5 antibodies prior to virus injection without reducing the magnitude of the anti-tumor effect. Preexisting anti-Ad5 neutralizing antibodies may therefore be an advantage rather than an issue in the clinical use of this new therapy.
- Subjects :
- Animals
Carcinoma, Hepatocellular therapy
Colorectal Neoplasms therapy
Dose-Response Relationship, Drug
Escherichia coli enzymology
Head and Neck Neoplasms therapy
Humans
Liver Neoplasms therapy
Luciferases metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Prostatic Neoplasms therapy
Transduction, Genetic
Transfection
Tumor Cells, Cultured
Adenoviridae genetics
Antineoplastic Agents therapeutic use
Aziridines therapeutic use
Gene Transfer Techniques
Genetic Therapy methods
Nitroreductases genetics
Prodrugs therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0016
- Volume :
- 3
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 11237680
- Full Text :
- https://doi.org/10.1006/mthe.2000.0250