Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Palmer
Daniel H
DH
Cancer Research UK Institute for Cancer Studies, Department of Pathology and Liver Research Laboratories, University of Birmingham, UK.
Mautner
Vivien
V
Mirza
Darius
D
Oliff
Simon
S
Gerritsen
Winald
W
van der Sijp
Joost R M
JR
Hubscher
Stefan
S
Reynolds
Gary
G
Bonney
Sarah
S
Rajaratnam
Ratna
R
Hull
Diana
D
Horne
Mark
M
Ellis
John
J
Mountain
Andrew
A
Hill
Simon
S
Harris
Peter A
PA
Searle
Peter F
PF
Young
Lawrence S
LS
James
Nicholas D
ND
Kerr
David J
DJ
D000256:Adenoviridae / Q000235:genetics* / Q000472:pathogenicity; D000368:Aged; D001388:Aziridines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000556:secondary*; D015179:Colorectal Neoplasms / Q000473:pathology*; D018736:DNA Adducts; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000494:pharmacology*; D005260:Female; D005420:Flavoproteins; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009601:Nitroreductases / Q000235:genetics* / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage* / Q000627:therapeutic use*; D019076:Transgenes; D014779:Virus Replication
D001388:Aziridines; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D005420:Flavoproteins; D011355:Prodrugs; C100099:tretazicar; C116053:NfsA protein, E coli; D009601:Nitroreductases