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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.

Original publication

DOI

10.1006/mthe.2000.0250

Type

Journal article

Journal

Mol Ther

Publication Date

02/2001

Volume

3

Pages

233 - 240

Keywords

Adenoviridae, Animals, Antineoplastic Agents, Aziridines, Carcinoma, Hepatocellular, Colorectal Neoplasms, Dose-Response Relationship, Drug, Escherichia coli, Gene Transfer Techniques, Genetic Therapy, Head and Neck Neoplasms, Humans, Liver Neoplasms, Luciferases, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Nitroreductases, Prodrugs, Prostatic Neoplasms, Transduction, Genetic, Transfection, Tumor Cells, Cultured