Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model

Freytag, Svend O.; Paielli, Dell; Wing, Mark S.; Rogulski, Ken; Brown, Stephen L.; Kolozsvary, Andrew; Seely, John C.; Barton, Kenneth; Dragovic, Alek; Kim, Jae Ho

doi:10.1016/s0360-3016(02)03005-5

Cited by 68 publications

(32 citation statements)

References 23 publications

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“…Such studies have used both adenoviral and herpes simplex viral vectors. [11][12][13][14][15][16][17][18][19][20] The virus-prodrug systems that have been used have Nitroreductase/CB1954 plus radiotherapy CL White et al focussed largely on HSVtk and ganciclovir and/or E. coli cytosine deaminase/uracil phosphoribosyltransferase and 5-fluorocytosine. These systems have shown significant advantages in terms of both in vitro and in vivo cell killing.…”

Section: Discussionmentioning

confidence: 99%

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

et al. 2007

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Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC 50 ¼ 0.35 mM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiationinduced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4 0 ,6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

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Section: Discussionmentioning

confidence: 99%

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

et al. 2007

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“…Although this has been somewhat successful in that increased efficacy has been obtained in some tumor models (36), but not in others (37), it has been reported that the converted metabolites of prodrugs are detrimental to oncolytic activity (38) as the viruses do not seem to replicate as well in the presence of agents that affect cell division. We made similar observations in that when the tumor cells were transduced with the replicative adenovirus vectors, the level of viral protein expressed was reduced in the presence of the prodrug (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Improvement of Antitumor Activity by Gene Amplification with a Replicating but Nondisseminating Adenovirus

et al. 2007

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Gene therapy is a promising approach for cancer treatment; however, efficacy of current vectors remains insufficient. To improve the success of suicide gene therapy, we constructed a replication-competent adenoviral vector that has its protease gene deleted and expresses bacterial cytosine deaminase fused with bacterial uracil phosphoribosyltransferase (CU). The prodrug, 5-fluorocytosine, is transformed into the highly toxic and tissue-diffusible 5-fluorouracil by CU in infected cells. This vector is incapable of producing infectious particles but is able to undergo a single round of replication, thereby increasing transgene copy number and expression. In the presence of 5-FC, compared with the first-generation vector (AdCU), the replication-competent vector, Ad(dPS)CU-IRES-E1A, was significantly more efficacious for in vitro tumor cell killing and in bystander assays, whereas 25-fold fewer viral particles were required in a three-dimensional spheroid model. For in vivo experiments, in which virus was injected into preestablished intracranial glioma xenografts, followed by 5-FC treatment, mice receiving Ad(dPS)CU-IRES-E1A had significantly smaller tumors at 35 days postinjection as well as significantly longer median survival than mice treated with the replication-deficient, protease-deleted vector [Ad(dPS)CU]. In an immunocompetent syngeneic model, Ad(dPS)CU + 5-FC-treated mice had a median survival of only 23 days, whereas Ad(dPS)CU-IRES-E1A + 5-FCtreated animals had a survival of 57.1% at 365 days. In conclusion, Ad(dPS)CU-IRES-E1A in the presence of 5-FC produces more potent tumoricidal effects than its replicationdeficient counterparts. [Cancer Res 2007;67(7):3387-95]

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“…Recently, Freytag et al described a replication competent adenovirus with a suicide gene and oncolytic viral therapy with radiotherapy. They demonstrated that the suicide genes CD and HSV-TK could augment the anti-tumor effects of replication competent adenoviruses and sensitize tumor cells to ionizing radiation [23,[34][35][36][37][38]. However, Freytag's virus cannot be used to treat metastatic disease and its tumor-specific replication is questionable.…”

Section: Discussionmentioning

confidence: 99%

Development of a Gene Therapy Trial for Metastatic Prostate Cancer

Gardner¹

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). This suicide gene (HSV-TK) and pro-drug (ganciclovir (GCV)) combination has been extensively explored in both preclinical and clinical studies. In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated both safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using replication defective adenovirus in treating prostate cancer metastasis. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro, the growth of an androgen-independent PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 µg/ml), compared to AdIU1 treatment alone. On the other hand, AdE4PSESE1a (a PRRA lacking HSV-TK) with and without GCV (10 µg/ml) treatment demonstrated similar in vitro cytotoxicity as AdIU1 alone. In vitro cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C 4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a or AdE4PSESE1a plus GCV. In summary, we have developed a novel therapeutic strategy for the treatment of AI prostate cancer.

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Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model

Cited by 68 publications

References 23 publications

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

Improvement of Antitumor Activity by Gene Amplification with a Replicating but Nondisseminating Adenovirus

Development of a Gene Therapy Trial for Metastatic Prostate Cancer

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