Transcriptional tumor‐selective promoter targeting of <i>E. coli</i> purine nucleoside phosphorylase for pancreatic cancer suicide gene therapy

Deharvengt, Sophie J.; Wack, Séverine; Aprahamian, Marc; Hajri, Amor

doi:10.1002/jgm.701

Cited by 18 publications

(10 citation statements)

References 31 publications

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“…Pancreatic cancer-specific cytotoxicity has been achieved in several in vitro and in vivo studies using tumor cell-specific promoters such as carcinoembryonic antigen (CEA), erb-B2, cyclooxygenase-2, Mucin1 (MUC1), and cholecystokinin type A receptor (CCKAR) to drive suicide genes [27][28][29][30][31][32][33]. The insulin gene promoter is a tissue-specific promoter, which is only activated in beta cells of the pancreas.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Cytotoxicity of RIPTK Gene Therapy of Pancreatic Cancer via PDX-1 Co-Delivery

Liu

Wang

Brunicardi

2007

Journal of Surgical Research

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Section: Introductionmentioning

confidence: 99%

Enhanced Cytotoxicity of RIPTK Gene Therapy of Pancreatic Cancer via PDX-1 Co-Delivery

Liu

Wang

Brunicardi

2007

Journal of Surgical Research

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“…Promoter-driven DNA delivery has been tested in a variety of tumor types using both viral (27,(36)(37)(38) and nonviral vectors (6,10,39). With the former type, coding sequences for metabolic enzymes are typically delivered (e.g., thymidine kinase or cytosine deaminase) to tumor cells, and these expressed enzymes activate prodrugs [ganciclovir (38) and 5-fluorocytosine (40), respectively].…”

Section: Discussionmentioning

confidence: 99%

MUC1 Promoter–Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer

Tholey

Lal

Jimbo

et al. 2015

Molecular Cancer Research

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Mucin1 (MUC1) is overexpressed in pancreatic ductal adenocarcinoma (PDA) and is associated with tumor aggressiveness, suggesting that MUC1 is a promising therapeutic target for promoter-driven diphtheria toxin A (DTA). Endogenous MUC1 transcript levels were analyzed by quantitative PCR (qPCR) in multiple PDA cells (Capan1, HPAFII, Su.86.86, Capan2, Hs766T, MiaPaCa2, and Panc1). Expression levels were correlated with luciferase activity and cell death after transfection with MUC1 promoter-driven luciferase and DTA constructs. MUC1-positive (þ) cells had significantly elevated MUC1 mRNA expression compared with MUC1-negative (À) cells. Luciferase activity was significantly higher in MUC1 þ cells when transfected with MUC1 promoter-driven luciferase and MUC1 þ cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter-driven DTA. IFNg pretreatment enhanced MUC1 expression in MUC1 À cells and induced sensitivity to MUC1-DTA therapy. Matched primary and metastatic tumor lesions from clinical specimens revealed similar MUC1 IHC labeling patterns, and a tissue microarray of human PDA biopsies revealed increased immunolabeling with a combination of MUC1 and mesothelin (MSLN) antibodies, compared with either antibody alone. Combining MUC1 with MSLN-targeted DTA enhanced drug efficacy in an in vitro model of heterogeneous PDA. These data demonstrate that MUC1 promoter-driven DTA preferentially kills MUC1-expressing PDA cells and drugs that enhance MUC1 expression sensitize PDA cells with low MUC1 expression.Implications: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter-driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs. Mol Cancer Res; 13(3); 439-48. Ó2014 AACR.

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“…To make SC36 safer for clinical trials, it should be important to develop tumor-specific expression vectors. Deharvengt et al 27 examined the feasibility of a tumor-specific targeting strategy to treat pancreatic cancer by using the human CEA and MUC1 promoters. Cai et al 29 demonstrated the killing effect of PNP/MePdR suicide gene system driven by an AFP promoter AF0.3 on AFP-positive hepatoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21] The ePNP/ MePdR system differs from other GDEPT systems, because the toxic metabolites of this system will readily cross the cell membrane and not require direct cell-to-cell contact or the presence of a gap junction. 22 In previous papers, the ePNP/MePdR system has been reported to be an efficient suicide gene/prodrug system with significant antitumor activities on ovarian cancers, 17 gliomas, 23 prostate cancers, 24 melanomas, 25 pancreatic cancers, 26,27 hepatomas 28,29 and bladder tumors. 30 However, an exploitation of this method using attenuated Salmonella as a carrier to deliver the ePNP gene has never been attempted.…”

Section: Introductionmentioning

confidence: 99%

Synergistic antitumor efficacy of suicide/ePNP gene and 6-methylpurine 2′-deoxyriboside via Salmonella against murine tumors

Lan

et al. 2008

Cancer Gene Ther

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Some anaerobes and facultative anaerobes have been used in tumor-specific gene therapy by reason of their selective growth in tumors. In this work, we aimed to evaluate the anticancer efficacy of attenuated Salmonella typhimurium as a carrier to deliver the Escherichia coli purine nucleoside phosphorylase (ePNP) gene for GDEPT (gene-directed enzyme-prodrug therapy). A live attenuated purine-auxotrophic strain of S. typhimurium (SC36) was used to carry the pEGFP-C1-ePNP vector that contains a green fluorescent protein (GFP) and an ePNP gene under the control of the human cytomegalovirus (CMV) promoter. The function of the ePNP expression vector was confirmed in vitro using the enzymic conversion of 6-methylpurine 2 0 -deoxyriboside (MePdR) into 6-methylpurine. We also observed a high bystander effect induced by the ePNP/MePdR system with a very low proportion (1%) of ePNP-positive cells. The killing effect and increased apoptosis induced by SC/ePNP (SC36 carrying the ePNP expression vector) infection were detected by cytotoxicity assay and PI staining flow cytometry analysis, in combination with MePdR administration. Furthermore, SC/ePNP was administered orally into mice bearing melanomas or pulmonary tumors, and its anti-tumor effect was evaluated. When the tumor was huge (500 mm 3 ) at the beginning of MePdR administration, SC/ePNP plus MepdR significantly inhibited tumor growth by about 59-80% and prolonged survival of mice. Complete tumor regression and long-term cure were achieved by MePdR administration, even when the tumor was large (100 mm 3 ) at the beginning of MePdR treatment. Our data support a hopeful view that tumor-targeting SC36 could improve antitumor efficacy of the ePNP/MePdR system due to its preferential accumulation and anticancer activity in tumors.

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Transcriptional tumor‐selective promoter targeting of E. coli purine nucleoside phosphorylase for pancreatic cancer suicide gene therapy

Cited by 18 publications

References 31 publications

Enhanced Cytotoxicity of RIPTK Gene Therapy of Pancreatic Cancer via PDX-1 Co-Delivery

Enhanced Cytotoxicity of RIPTK Gene Therapy of Pancreatic Cancer via PDX-1 Co-Delivery

MUC1 Promoter–Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer

Synergistic antitumor efficacy of suicide/ePNP gene and 6-methylpurine 2′-deoxyriboside via Salmonella against murine tumors

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