Virus-Directed Enzyme Prodrug Therapy: Intratumoral Administration of a Replication-Deficient Adenovirus Encoding Nitroreductase to Patients With Resectable Liver Cancer

Palmer, Daniel H.; Mautner, Vivien; Mirza, Darius F.; Oliff, Simon; Gerritsen, Winald R.; Sijp, Joost R.M. van der; Hübscher, Stefan G.; Reynolds, Gary; Bonney, Sarah; Rajaratnam, Ratna; Hull, Diana; Horne, Mark; Ellis, John R.; Mountain, Andrew; Hill, Susan; Harris, Peter A.; Searle, Peter F.; Young, Lawrence S.; James, Nicholas D.; Kerr, David

doi:10.1200/jco.2004.10.005

Cited by 117 publications

(82 citation statements)

References 15 publications

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“…23 Clinical trials with NTR/CB1954 started in late 1990s when pharmacokinetics of CB1954 was tested in a phase I study on patients with primary and secondary liver tumors. 24 More recently, a replication-defective adenoviral vector CTL102 encoding gene has been used on patients with primary or secondary liver cancer 25 and prostate cancer. 8,26 However, there are many challenges yet to be overcome for it to be considered a robust therapy.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals

et al. 2011

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Gene-directed enzyme prodrug therapy (GDEPT) is a promising and emerging strategy that attempts to limit the systemic toxicity inherent to cancer chemotherapy by means of tumor-targeted delivery and expression of an exogenous gene whose product converts nontoxic prodrug(s) into activated cytotoxic agent(s). The bacterial nitroreductase (NTR) enzyme, coupled with its substrate prodrug 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), is a promising GDEPT strategy that has reached clinical trials. However, no strategy exists to visually monitor and quantitatively evaluate the therapeutic efficacy of NTR/CB1954 prodrug therapy in cells and imaging in living animals. As the success of any GDEPT is dependent upon the efficiency of transgene expression in vivo, we developed a safe, sensitive and reproducible noninvasive imaging method to monitor NTR transgene expression that would allow quantitative assessment of both therapeutic efficacy and diagnostic outcome of NTR/ CB1954 prodrug therapy in the future. Here, we investigate the use of a novel fluorescent imaging dye CytoCy5S (a Cy5-labeled quenched substrate of NTR enzyme) on various cancer cell lines in vitro and in NTR-transfected tumor-bearing animals in vivo. CytoCy5S-labeled cells become fluorescent at 'red-shifted' wavelengths (638 nm) when reduced by cellular NTR enzyme and remains trapped within the cells for extended periods of time. The conversion and entrapment was dynamically recorded using a time-lapsed microscopy. Systemic and intratumoral delivery of CytoCy5S to NTR-expressing tumors in animals indicated steady and reproducible signals even 16 h after delivery (Po0.001). This is the first study to address visual monitoring and quantitative evaluation of NTR activity in small animals using CytoCy5S, and establishes the capability of NTR to function as an imageable reporter gene.

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Section: Discussionmentioning

confidence: 99%

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals

et al. 2011

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“…However, results of clinical trials have shown that, among other challenges, poor in vivo gene transfer efficiency poses a major obstacle for those approaches that rely on in vivo gene transfer into tumor cells. [1][2][3][4][5][6][7][8] This applies to 'suicide gene' therapy, oncogene antagonism, antiangiogenesis gene therapy and some forms of immunotherapy. Thus, intense efforts are being directed at modifying vectors and delivery systems in order to improve gene transfer.…”

Section: Introductionmentioning

confidence: 99%

Enriching suicide gene bearing tumor cells for an increased bystander effect

et al. 2006

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The success of cancer gene therapies requiring in vivo gene transfer is severely hampered by the low efficacy of gene transfer, which has been difficult to improve. We therefore established a novel strategy to increase the share of transduced cells post gene transfer. We hypothesized that in vivo selection of tumor cells transduced with a suicide gene effectively enriches these cells within a tumor, thus allowing for an increased bystander effect after the prodrug is given, leading to enhanced eradication of tumor cells. We reasoned that in vivo enrichment should be achieved by exploiting the metabolism of the suicide gene product. For this 'enrichment-eradication' strategy we chose a fusion gene of cytosine deaminase and uracil phosphoribosyl transferase. Positive selection (enrichment) was to be achieved by concurrently giving N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis, which leads to pyrimidine depletion-mediated death of non-transduced cells, and cytosine, to rescue fusion gene expressing cells via the pyrimidine salvage pathway. Negative selection (eradication) was to be induced by giving the prodrug 5-fluorocytosine. Indeed, murine NXS2 neuroblastoma cells transduced with the fusion gene were effectively enriched in vitro, leading to a near-complete bystander effect. In vivo enrichment-eradication of NXS2 cells led to decreased tumor growth. This proof-of-principle study shows that enrichment-eradication may compensate the effects of low in vivo gene transfer efficacy, a major obstacle in cancer gene therapy.

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“…[11][12][13][14][15] Dissemination into the circulation following IT injection has already been reported in both animal studies and clinical trials. [16][17][18] For example Wang et al (2006) 19 explored injecting 20 or 50 ml of adenovirus solution IT, using an infusion rate of 1.0 ml s À1 . With all injectate volumes there was considerable hepatic transduction, particularly at higher virus doses, implying shedding of viable virus from the tumour into the circulation although virus particle kinetics were not measured directly.…”

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confidence: 99%

Factors influencing retention of adenovirus within tumours following direct intratumoural injection

et al. 2008

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Virus-Directed Enzyme Prodrug Therapy: Intratumoral Administration of a Replication-Deficient Adenovirus Encoding Nitroreductase to Patients With Resectable Liver Cancer

Cited by 117 publications

References 15 publications

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals

Enriching suicide gene bearing tumor cells for an increased bystander effect

Factors influencing retention of adenovirus within tumours following direct intratumoural injection

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