Chimeric PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors

Wu, Lihua; Matherly, Jamie; Smallwood, Andrea; Jy, Adams; Billick, Erika; Belldegrun, Arie S.; Carey, Michael

doi:10.1038/sj.gt.3301549

Cited by 96 publications

(85 citation statements)

References 48 publications

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“…Previously, it was reported that use of promoter and expression regulatory elements of tumoror tissue-specific molecules, such as -fetoprotein, carcinoembryonic antigen, human telomerase reverse transcriptase and prostate-specific antigen, successfully regulated the expression of transgenes in a tumor-or tissue-specific fashion after systemic gene transfer using adenoviral vector. [52][53][54][55] Therefore, these targeting techniques of adenovirus-based vectors will further improve our combination strategy.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Saitô

Murata

Watanabe

et al. 2005

Intl Journal of Cancer

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Previous studies demonstrated that IL-13Ra2 chain-overexpressing cancer cells were highly sensitive to IL-13 cytotoxin (IL13-PE38QQR) and could be targeted by cytotoxin treatment. However, the majority of human tumors do not express high levels of IL-13Ra2 chain. To expand the IL-13 cytotoxin-mediated cancer targeting therapy, we combined cytotoxin treatment with gene transfer of IL-13Ra2 chain. We constructed a recombinant adenoviral vector carrying the human IL-13Ra2 gene (Ad-IL-13Ra2), which expresses high levels of IL-13Ra2 chain on infected cells. Human cancer cell lines A549 and HOS, which originally show no IL-13Ra2 expression and little sensitivity to IL-13 cytotoxin, were effectively converted to become sensitive to this cytotoxin after Ad-IL-13Ra2 infection. The CC 50 of IL-13 cytotoxin for Ad-IL13Ra2-infected A549 cells was <10 ng/ml, whereas the CC 50 for uninfected or control vector-infected cells was >500 ng/ml. We also examined the antitumor activity of IL-13 cytotoxin in an established xenograft model of cytotoxin-resistant human lung tumor. Only a single i.t. injection of Ad-IL-13Ra2 markedly enhanced the sensitivity of established tumors to IL-13 cytotoxin treatment; furthermore, this antitumor effect was significantly sustained for more than 1 month after the last treatment with IL-13 cytotoxin. Taken together, these results suggest the combination of adenoviral vector-mediated IL-13Ra2 gene transfer and IL-13 cytotoxin administration can be an effective targeting approach for several types of IL-13 cytotoxin-resistant cancers which show no or little expression of IL-13Ra2 chain. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Saitô

Murata

Watanabe

et al. 2005

Intl Journal of Cancer

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“…Previous GDEPT studies for CaP have used regulatory sequences with no tissue-specific tropism, such as the RSV promoter 3,5 or sequences that provide prostate-specific expression. The latter have included promoters and/or enhancers of prostate-specific antigen, PSA, 22,23 osteocalcin, 24 caveolin 25 and Pb 20 genes. Our previous transfection studies had identified that the PSME plus the Pb promoter generated high level expression in prostate cells.…”

Section: Discussionmentioning

confidence: 99%

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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“…Due to its highly specific nature, the PSA promoter has been frequently used in prostate cancer-targeted gene therapy approaches [3,15,16]. A modified PSA promoter-driven luciferase reporter adenoviral vector construct showed preferential expression in prostate gland and tumors, by three orders of magnitude, compared with liver tissue [17,18]. Human α-lactalbumin (hALA) is an enzyme involved in lactose production, and it is expressed in the lactating mammary gland and in a high proportion of breast cancer cases [19].…”

Section: Transcriptional Targetingmentioning

confidence: 99%

“…For example, the activity of native PSA promoter and enhancer (PSE) can be augmented by modifying the androgen receptor (AR) elements, which serve key activating functions for the PSA gene [15,16]. By insertion of four tandem copies of the synthetic androgen-responsive element, or by duplication of a 400-base pair enhancer core element, a nearly 20-fold enhancement of activity over the parental PSE was achieved [17]. Similar approaches have been successful in improving the activity of the tyrosinase promoter [14] and the CEA promoter [42].…”

Section: Augmenting Cancer-specific Expressionmentioning

confidence: 99%

Transcriptionally targeted gene therapy to detect and treat cancer

Wu¹,

Johnson²,

Sato³

2003

Trends in Molecular Medicine

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The greatest challenge in cancer treatment is to achieve the highest levels of specificity and efficacy. Cancer gene therapy could be designed specifically to express therapeutic genes to induce cancer cell destruction. Cancer-specific promoters are useful tools to accomplish targeted expression; however, high levels of gene expression are needed to achieve therapeutic efficacy. Incorporating an imaging reporter gene in tandem with the therapeutic gene will allow tangible proof of principle that gene expression occurs at the correct location and at a sufficient level. Gene-based imaging can advance cancer detection and diagnosis. By combining the cancer-targeted imaging and therapeutic strategies, the exciting prospect of a 'one-two punch' to find hidden, disseminated cancer cells and destroy them simultaneously can potentially be realized.Multiple genetic alterations that confer growth advantages to tumor cells are accumulated during the transformation from normal to neoplastic growth [1]. The loss of growth suppressive genes or gain of oncogenes constitutes a common mechanism of oncogenesis. Based on this information, a rational therapeutic approach is to re-introduce the defective growth control genes into tumor cells. In addition, approaches of inducing apoptotic responses and enhancing anti-tumor immune responses have also been employed [2]. Due to the availability of multiple flexible therapeutic strategies, gene therapy is being actively investigated in clinical settings.Among the ~ 40 ongoing gene therapy clinical trials for cancer (searched via www.clinicaltrials.gov/), 18 of the trial protocols involve an immune activating scheme, ten studies employ a genetic correction strategy and five use a cytotoxic gene. With regard to genetic correction strategies, p53 is a major target. The recombinant adenovirus is the dominant viral gene delivery vector, and it is employed in 18 protocols. However, none of 40 protocols use a cancer-specific gene expression strategy. An oncolytic adenovirus CN706 containing prostate-specific antigen (PSA) promoter driven viral replication [3] is being evaluated in phase II clinical trial for prostate cancer [4].Because the goal of cancer gene therapy is to eradicate cancer cells, many therapeutic genes could be detrimental if unintentionally expressed in normal cells. Selectively targeting the cancer cells is useful to achieve safety and efficacy, especially when the gene therapy vector is directly delivered into patients. Based on features that distinguish cancerous from normal cells, three targeting strategies could be employed. Transcriptional targeting takes advantage of the fact that some cancer cells express a subset of exclusive genes, and uses these cancerspecific promoters to express the desired transgenes [5]. Transductional targeting refers to surface modification on the gene delivery vehicle to enhance interactions with the cancer cell membrane antigen, thereby improving gene transfer into the cancerous cell. A third promising approach is to exploit cancer-a...

show abstract

Chimeric PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors

Cited by 96 publications

References 48 publications

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

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

Transcriptionally targeted gene therapy to detect and treat cancer

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