Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

Voeks, Dale J.; Martiniello‐Wilks, Rosetta; Madden, Joah R.; Smith, Kathryn F.; Bennetts, E; Gw, Both; Russell, Pamela J.

doi:10.1038/sj.gt.3301698

Cited by 56 publications

(75 citation statements)

References 41 publications

(52 reference statements)

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“…[9][10][11][12] In addition, the legitimacy of the overall PNP-GDEPT strategy has been well documented. 17,20,21 In this study where vector was delivered intratumorally, there was no histological evidence of treatment toxicity in liver, spleen, kidney, lung or gut. OAdV623 also successfully delivered PNP/fludarabine-GDEPT to both AS and AI human CaP xenografts producing retarded tumor growth, increased tumor doubling times and host survival.…”

Section: Discussionmentioning

confidence: 60%

“…17 As previously mentioned, the vectors have a favorable biosafety profile in human cells with respect to replication, transformation and complementation. [9][10][11][12] In addition, the legitimacy of the overall PNP-GDEPT strategy has been well documented.…”

Section: Discussionmentioning

confidence: 98%

“…Issues concerning the dose of fludarabine used in mice have previously been discussed. 17 Mice have a fludarabine tolerance around 45 times higher than man, possibly related to their contrasting distribution in the body of deaminase and phosphorylation enzymes that breakdown or metabolize fludarabine. 27,28 The effective dose of 75 mg/m 2 / day for 5 days used in this work was only three times the dose used in humans and was much lower than that used to treat mice bearing PNP-transfected glioma cell tumors.…”

Section: Discussionmentioning

confidence: 99%

“…4,17 Fludarabine alone also did not significantly affect LN3 tumor growth compared to vehicle control ( Figure 3a). Tumor volume in the GDEPT group was suppressed from day 15 through day 24, and in the resulting % tumor growth inhibition analysis, this reached statistical significance on day 22 (Po0.05; Table 2).…”

Section: Gdept Efficacy On As Ln3 Tumor Growthmentioning

confidence: 95%

“…Our previous studies with PNP-GDEPT demonstrated marked suppression of an aggressive murine CaP in immunocompetent mice. 17 We isolated an enhancer (PSME) from the third intron of the prostate-specific membrane antigen (PSMA) gene, FOLH1 (folate hydrolase gene). 7 PSME promoted high level expression in CaP cell lines, but was essentially inactive or repressed expression in nonprostate cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

et al. 2004

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Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostatedirected promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and nonCaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m 2 /day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for 46 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and 450% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Gdept Efficacy On As Ln3 Tumor Growthmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

et al. 2004

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Directed Enzyme Prodrug Therapies

Niculescu‐Duvaz

Negoita‐Giras

Niculescu‐Duvaz³

et al. 2010

Prodrugs and Targeted Delivery

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Gene Transfer to Mouse Testes by Electroporation and Its Influence on Spermatogenesis

Umemoto

Sasaki

Kojima

et al. 2005

Journal of Andrology

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We transferred the adventitious gene pCAGGS-lacZ to mouse testes with the use of a square-wave electroporator and investigated the efficiency of gene transfer (GT) and the influence of the procedure on testicular damage and spermatogenesis. Mice were divided into 5 groups: (1-2) injection of gene/phosphate-buffered saline (PBS) into the interstitial space followed by electroporation (EP), (3) EP alone, (4-5) injection of gene/PBS without EP. The presence of the lacZ gene was determined by X-gal (5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside) staining and the polymerase chain reaction (PCR). The influence of transfer on spermatogenesis was assessed by evaluating the seminiferous tubules according to the Johnsen score (JS). TdT-mediated dUTP-biotin nick end-labeling (TUNEL) staining was performed for the detection of apoptosis in the testes to evaluate the testicular damage caused by GT, and fertilization ability was assessed by mating male mice from each group with normal female mice at 1, 2, 4, 6, and 8 weeks after the procedure. LacZ expression was detected by X-gal staining and PCR for 4 weeks after GT in group 1. But in group 4, LacZ expression was not detected for all times. In groups 1 through 3, the JSs decreased gradually until 4 weeks and recovered at 6 and 8 weeks after GT. The JSs were significantly decreased at 4 weeks for groups 1 through 3 compared with groups 4 and 5. In groups 1 through 3, apoptotic cells were significantly more numerous at 1, 2, and 4 weeks after the procedure, and there were significant differences in their numbers between groups 1 through 3 and groups 4 and 5 until 4 weeks after the procedure. The number of offspring did not differ significantly between all groups. These results suggest that although spermatogenic damage caused by EP could present problems, GT by EP might be effective for transfecting germ cells or somatic cells and could be applicable for in vivo gene therapy for male infertility in the future.

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Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

Abstract: A gene-directed enzyme pro-drug therapy (GDEPT) based on purine nucleoside phosphorylase (PNP)

Cited by 56 publications

References 41 publications

Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

Directed Enzyme Prodrug Therapies

Gene Transfer to Mouse Testes by Electroporation and Its Influence on Spermatogenesis

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