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

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Virus directed enzyme prodrug therapy: Intratumoural administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. / Palmer, Daniel; Mautner, Vivien; Mirza, Darius; Oliff, S; Gerritsen, W; van der Sijp, JR; Hubscher, Stefan; Reynolds, Gary; Bonney, Sarah; Rajaratnam, R; Hull, Diana; Horne, M; Ellis, J; Mountain, Andrew; Hill, Seran; Harris, PA; Searle, Peter; Young, Lawrence; James, Nicholas; Kerr, DJ.

In: Journal of Clinical Oncology, Vol. 22, 29.03.2004, p. 1546-1552.

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Palmer, Daniel ; Mautner, Vivien ; Mirza, Darius ; Oliff, S ; Gerritsen, W ; van der Sijp, JR ; Hubscher, Stefan ; Reynolds, Gary ; Bonney, Sarah ; Rajaratnam, R ; Hull, Diana ; Horne, M ; Ellis, J ; Mountain, Andrew ; Hill, Seran ; Harris, PA ; Searle, Peter ; Young, Lawrence ; James, Nicholas ; Kerr, DJ. / Virus directed enzyme prodrug therapy: Intratumoural administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. In: Journal of Clinical Oncology. 2004 ; Vol. 22. pp. 1546-1552.

Bibtex

@article{bd4e5f51264e4397bccb224095f3c7b0,
title = "Virus directed enzyme prodrug therapy: Intratumoural administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer",
abstract = "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.",
author = "Daniel Palmer and Vivien Mautner and Darius Mirza and S Oliff and W Gerritsen and {van der Sijp}, JR and Stefan Hubscher and Gary Reynolds and Sarah Bonney and R Rajaratnam and Diana Hull and M Horne and J Ellis and Andrew Mountain and Seran Hill and PA Harris and Peter Searle and Lawrence Young and Nicholas James and DJ Kerr",
year = "2004",
month = mar,
day = "29",
doi = "10.1200/JCO.2004.10.005",
language = "English",
volume = "22",
pages = "1546--1552",
journal = "Journal of Clinical Oncology ",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",

}

RIS

TY - JOUR

T1 - Virus directed enzyme prodrug therapy: Intratumoural administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer

AU - Palmer, Daniel

AU - Mautner, Vivien

AU - Mirza, Darius

AU - Oliff, S

AU - Gerritsen, W

AU - van der Sijp, JR

AU - Hubscher, Stefan

AU - Reynolds, Gary

AU - Bonney, Sarah

AU - Rajaratnam, R

AU - Hull, Diana

AU - Horne, M

AU - Ellis, J

AU - Mountain, Andrew

AU - Hill, Seran

AU - Harris, PA

AU - Searle, Peter

AU - Young, Lawrence

AU - James, Nicholas

AU - Kerr, DJ

PY - 2004/3/29

Y1 - 2004/3/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=2442696806&partnerID=8YFLogxK

U2 - 10.1200/JCO.2004.10.005

DO - 10.1200/JCO.2004.10.005

M3 - Article

C2 - 15051757

VL - 22

SP - 1546

EP - 1552

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

ER -