Targeted Gene Therapy for Ovarian Cancer

Rocconi, Rodney P.; Numnum, T. Michael; Stoff-Khalili, Mariam A.; Makhija, Sonia K.; Alvarez, Ronald D.; Curiel, David T.

doi:10.2174/156652305774964668

Cited by 20 publications

(21 citation statements)

References 58 publications

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“…3,6 As therapy efficacy was shown to correlate strongly with the ability of the virus to enter into cancer cells, expression and function of the coxsackie-adenovirus-receptor (hCAR), which is the primary receptor of group C adenoviruses, were studied extensively. hCAR was shown to be differently expressed in various tumor entities, and at least in ovarian cancer immunohistochemical investigations revealed a marked distributional heterogeneity with regard to focal positivity and negativity in the same tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, great effort has been undertaken in developing alternative therapy strategies, such as gene therapy via adenovirus vector systems. [2][3][4][5][6] As trans-gene delivery and thus therapy efficacy correlates with susceptibility to transduction, [7][8][9][10] expression and function of the full-length form of the membranous human coxsackie adenovirus receptor (hCAR), which is the primary attachment protein for adenovirus entry into the cell, has been extensively studied during recent years. CAR belongs to the immunoglobulin superfamily.…”

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confidence: 99%

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Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

Reimer

Steppan

Wiedemair

et al. 2007

Intl Journal of Cancer

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The coxsackie‐adenovirus receptor (hCAR) has been extensively studied in context of adenoviral‐based gene therapy for cancer. However, there is strong evidence that besides its decisive role in coxsackie and adenovirus cell‐entry, hCAR is a component of epithelial tight junctions and involved in cell‐cell adhesions in normal and cancer cells. Furthermore, this adhesion molecule behaves like a cell surface receptor endowed with tumor suppressive properties via signal transduction. Moreover, 3 truncated soluble isoforms of hCAR were recently identified. We investigated the quantitative expression of all known CAR isoforms in a training set of 140 ovarian cancer samples and 21 controls by RT‐PCR. The expression levels of the various isoforms were compared with clinicopathologic parameters and their prognostic significance was assessed. Expression levels of all CAR isoforms were elevated in ovarian carcinomas as compared with those of non‐malignant controls. mRNA‐expression correlated with protein levels. Moreover, expression of the soluble isoforms CAR 3/7 and CAR 4/7 but not that of hCAR was significantly increased in advanced ovarian cancer as revealed by a highly significant correlation with FIGO stage and residual disease > 2 cm in diameter after debulking surgery. High expression of CAR 3/7 and 4/7 was shown to be of independent prognostic relevance for progression‐free (CAR 4/7) and overall survival (CAR 3/7 and CAR 4/7). In conclusion, soluble CAR isoforms 3/7 and 4/7 may play a pivotal role in ovarian cancer biology, possibly by counteracting migration‐ and growth‐inhibitory properties of the membranous hCAR and thus favoring cancer cell dissemination throughout the peritoneal cavity. © 2007 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

Reimer

Steppan

Wiedemair

et al. 2007

Intl Journal of Cancer

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“…Ovarian, pancreatic, and gastric cancers are particularly attractive targets for IP injections. [6,37,[39][40][41][42][43][44][45][46] In this study, for the first time, we comprehensively compare the transgene expression generated by IP injection of branched or linear PEI-pDNA nanoparticles using bioluminescent imaging (BLI). BLI is a modern transgene expression imaging technique from which the results strongly correlate to transgene expression results measured using traditional tissue and organ harvesting methodologies.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Intra¹,

Salem²

2008

Journal of Controlled Release

125

119

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Polyethylenimine (PEI) is a cationic polymer that has shown significant potential for delivering genes in vitro and in vivo. Mixing cationic PEI with negatively charged plasmid DNA (pDNA) results in the spontaneous electrostatic formation of stable nanoparticle complexes. The structure of PEI can be branched or linear. In this study, we show that branched PEI has a stronger electrostatic interaction with pDNA than linear PEI, which accounts for greater compaction, higher zeta potentials and smaller nanoparticle sizes at equivalent pDNA concentrations. For both linear and branched PEI, increasing the concentration of pDNA mixed in the same volume and at the same nitrogen to phosphate (N:P) ratio results in larger average particle sizes. Increasing the N:P ratio increases luciferase activity generated by branched PEI-pDNA nanoparticles and linear PEI-pDNA nanoparticles in HEK293, COS7 and HeLa cell lines. Increasing the N:P ratio at which branched PEI-pDNA nanoparticles are prepared also increases luciferase expression in HepG2 cells but does not increase luciferase expression generated by linear PEI-pDNA nanoparticles. In all of the cell lines, branched PEI-pDNA nanoparticles prepared at N:P ratios of 10 and above generated significantly higher luciferase activity than linear PEI-pDNA nanoparticles. Luciferase activity was highest in the HEK293 cells and luciferase expression in each of the cell lines followed the order of HEK293

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“…Experimental therapies for ovarian cancer have the common goal of decreasing disease burden in the peritoneal space and include the addition of new cytotoxic agents, immune stimulation agents, and antibody based treatments (6). The confinement of ovarian cancer to the peritoneal space suggests that adenovirus vectors could provide a new treatment approach (7,8). Delivery to the peritoneal space places the vector at high concentrations in close proximity to the target disease.…”

Section: Introductionmentioning

confidence: 99%

“…Improvements in selectivity of adenovirus vectors can be accomplished by manipulating the capsid proteins that bind to cellular receptors and facilitate cell entry (8,22). The primary receptor for adenovirus is the coxsackie adenovirus receptor (CAR) (23).…”

Section: Introductionmentioning

confidence: 99%

Experimental treatment of ovarian cancers by adenovirus vectors combining receptor targeting and selective expression of tumor necrosis factor

Murugesan

Akiyama²,

Einfeld³

et al. 2007

Int J Oncol

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Abstract. Ovarian cancer is the fourth most common cancer among women and existing treatment is not routinely curative. One new strategy for cancer therapy is the selective delivery of TNFα to tumors via adenovirus vectors. We have tested the combination of two modifications to adenovirus vectors designed to limit delivery to tumors, capsid modification and expression control. To target α v ß 3/5 integrin receptors that are highly expressed in tumor and sparsely expressed in the epithelial layer of peritoneum, we modified the capsid fiber and penton base to remove native receptor binding and incorporated an RGD-4C motif in the fiber knob (Ad.PB*F*RGD). This vector exhibits effective gene transfer in all of the α v ß 3/5 -positive ovarian cancer cells tested in vitro and in vivo. Importantly, the Ad.PB*F*RGD vector is able to transduce ovarian tumor nodules and avoid infecting the normal mesothelial cells that line the intraperitoneal space following intraperitoneal administration. To further increase selectivity, different promoters were incorporated into the capsid-modified vector to confer the expression of the hTNFα therapeutic gene. We analyzed both constitutive (CMV or RSV) and potentially tumor selective promoters (MUC-1, E2F or hTERT) in terms of efficacy, selectivity and safety. TNF-expressing Ad.PB*F*RGD vectors containing the MUC-1 promoter showed anti-tumor activity in two ovarian cancer xenograft models (Caov3 and Igr-ov1) with little evidence of toxicity or systemic TNF. The data indicate that combination of capsid modification and transcriptional regulation of expression is a promising strategy for development of a new ovarian cancer treatment.

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Targeted Gene Therapy for Ovarian Cancer

Cited by 20 publications

References 58 publications

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Experimental treatment of ovarian cancers by adenovirus vectors combining receptor targeting and selective expression of tumor necrosis factor

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