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PURPOSE: Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. PATIENTS AND METHODS: Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. RESULTS: Eighteen patients were treated with escalating doses of CTL102 (range, 10(8)-5 x 10(11) virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. CONCLUSION: Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 x 10(11) virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.

Original publication

DOI

10.1200/JCO.2004.10.005

Type

Journal article

Journal

J Clin Oncol

Publication Date

01/05/2004

Volume

22

Pages

1546 - 1552

Keywords

Adenoviridae, Aged, Aziridines, Carcinoma, Hepatocellular, Colorectal Neoplasms, DNA Adducts, Drug Resistance, Neoplasm, Escherichia coli Proteins, Female, Flavoproteins, Gene Expression Regulation, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Half-Life, Humans, Immunohistochemistry, Liver Neoplasms, Male, Middle Aged, Nitroreductases, Prodrugs, Transgenes, Virus Replication