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Salmons B.,Austrianova Singapore Pte Ltd | Brandtner E.M.,Austrianova Singapore Pte Ltd | Hettrich K.,Fraunhofer Institute for Applied Polymer Research | Wagenknecht W.,Fraunhofer Institute for Applied Polymer Research | And 6 more authors.
Current Opinion in Molecular Therapeutics | Year: 2010

One of the first strategies for cancer gene therapy was the use of suicide gene/prodrug combinations, originally delivered to tumor cells using viral vectors. A major limitation of this approach was the inefficiency of suicide gene delivery. An alternative strategy, in which the suicide genes are physically juxtaposed to the tumor, involves the implantation of encapsulated, genetically modified cells. Cell encapsulation technologies were originally developed for the treatment of acquired and genetic diseases, such as diabetes. In the application of this technology for the treatment of tumors, cells that are genetically modified to overexpress suicide genes are encapsulated and implanted near solid tumors; this process is then followed by systemic prodrug administration. This review discusses the various cells types, suicide genes and prodrugs that have been used in preclinical and clinical trials, as well as the data that have been obtained from these studies. Future improvements for the production of second-generation approaches are also discussed. © Thomson Reuters (Scientific) Ltd.


Hlavaty J.,University of Veterinary Medicine Vienna | Hlavaty J.,Christian Doppler Laboratory | Petznek H.,University of Veterinary Medicine Vienna | Holzmuller H.,University of Veterinary Medicine Vienna | And 8 more authors.
PLoS ONE | Year: 2012

Background: Gene-directed enzyme prodrug therapy (GDEPT) is a two-step treatment protocol for solid tumors that involves the transfer of a gene encoding a prodrug-activating enzyme followed by administration of the inactive prodrug that is subsequently activated by the enzyme to its tumor toxic form. However, the establishment of such novel treatment regimes to combat pancreatic cancer requires defined and robust animal model systems. Methods: Here, we comprehensively compared six human pancreatic cancer cell lines (PaCa-44, PANC-1, MIA PaCa-2, Hs-766T, Capan-2, and BxPc-3) in subcutaneous and orthotopical mouse models as well as in their susceptibility to different GDEPTs. Results: Tumor uptake was 83% to 100% in the subcutaneous model and 60% to 100% in the orthotopical mouse model, except for Hs-766T cells, which did not grow orthotopically. Pathohistological analyses of the orthotopical models revealed an infiltrative growth of almost all tumors into the pancreas; however, the different cell lines gave rise to tumors with different morphological characteristics. All of the resultant tumors were positive for MUC-1 staining indicating their origin from glandular or ductal epithelium, but revealed scattered pan-cytokeratin staining. Transfer of the cytochrome P450 and cytosine deaminase suicide gene, respectively, into the pancreatic cancer cell lines using retroviral vector technology revealed high level infectibility of these cell lines and allowed the analysis of the sensitivity of these cells to the chemotherapeutic drugs ifosfamide and 5-fluorocytosine, respectively. Conclusion: These data qualify the cell lines as part of valuable in vitro and in vivo models for the use in defined preclinical studies for pancreas tumor therapy. © 2012 Hlavaty et al.


Hlavaty J.,University of Veterinary Medicine Vienna | Hlavaty J.,Christian Doppler Laboratory | Jandl G.,University of Veterinary Medicine Vienna | Liszt M.,University of Veterinary Medicine Vienna | And 9 more authors.
Journal of Neuro-Oncology | Year: 2011

Despite impressive improvements in neurosurgical techniques, radiation and chemotherapy during the past few years, little progress has been made in the treatment of malignant gliomas. Recently, the efficacy of suicide gene therapy based on replication-competent retroviral (RCR) vectors as delivery vehicles for the therapeutic gene has been described in the treatment of experimental cancer, including gliomas. In this study, we have thus critically evaluated a panel of human and rodent glioma/glioblastoma cell lines (U-87MG, U-118MG, LN-18, LN-229, 8-MG-BA, 42-MG-BA, A-172, T-98G, UVW, C6, 9L, G-26, GL-261, Tu-2449, Tu-9648) with respect to RCR virus vector spread, sensitivity towards the cytosine deaminase (CD)/5-flurocytosine (5-FC)/5-flurouracil (5-FU) suicide system, and orthotopic growth characteristics in mice to identify suitable preclinical animal models for the development of a glioblastoma gene therapy. Rapid virus spread was observed in eight out of nine human cell lines tested in vitro. As expected, only CD-expressing cells became sensitive to 5-FC, due to their ability to convert the prodrug in its toxic form, 5-FU. All LD 50 values were within the range of concentrations obtained in human body fluids after conventional antifungal 5-FC administration. In addition, a significant bystander effect was observed in all human glioma cell lines tested. Injection of the RCR vector into pre-established orthotopic mouse tumor xenografts revealed substantial infection and virus spread of tumor tissue from most cell types. © 2010 Springer Science+Business Media, LLC.


Salmons B.,Austrianova Singapore Pte Ltd.
Advances in Experimental Medicine and Biology | Year: 2010

Although cell encapsulation technologies were originally developed for the treatment of acquired and genetic diseases such as diabetes, they can also be applied to the treatment of a variety of solid tumours. There are a number of strategies aimed at treating tumours with encapsulated cells and most of these are reviewed in this chapter. Many of these strategies have shown promise in preclinical studies and clinical trials. © 2010 Landes Bioscience and Springer Science+Business Media.


Patent
Austrianova Singapore Pte Ltd. | Date: 2012-01-25

A simple cellulose sulphate based microencapsulation technology has been applied to encapsulate bacterial or other microbial cells, which produce and release digestive enzymes and thereby provides an acid resistant shelter for these microbial cells. Surprisingly, the resulting spheres were found to provide sufficient protection for encapsulated cells from treatment with aqueous acidic solutions. Thereby the cellulose sulphate microencapsulated cells, such as probiotics are now enabled to survive passage, for example, through the stomach after consumption by a human or animal with a higher survival rate than those not within a microcapsule. After passing the stomach these cells are delivering products produced by them, e.g. enzymes or other nutrition factors. This technology therefore proves to be very useful in providing digestive or otherwise beneficial enzymes and/or of living microbial cells, into the lower gastrointestinal tract, where they could confer their health benefit to the host.


The disclosure provides a method of freeze-drying encapsulated cells, the method comprising at least two consecutive incubation steps, wherein the encapsulated cells are incubated in each incubation step in an incubation solution containing cryoprotectant over a suitable period of time, wherein the concentration of cryoprotectant in the incubation solution is increased with each subsequent incubation step. The disclosure also provides freeze dried cells that are obtained by this method as well as various uses of these cells as pharmaceutical, food additive or additive in cosmetics. The disclosure also provides a composition that contains skim milk, glycerol and a carbohydrate.


PubMed | Austrianova Singapore Pte Ltd.
Type: | Journal: Advances in experimental medicine and biology | Year: 2010

Although cell encapsulation technologies were originally developed for the treatment of acquired and genetic diseases such as diabetes, they can also be applied to the treatment of a variety of solid tumours. There are a number of strategies aimed at treating tumours with encapsulated cells and most of these are reviewed in this chapter. Many of these strategies have shown promise in preclinical studies and clinical trials.


PubMed | Austrianova Singapore Pte Ltd
Type: Journal Article | Journal: Current opinion in molecular therapeutics | Year: 2010

One of the first strategies for cancer gene therapy was the use of suicide gene/prodrug combinations, originally delivered to tumor cells using viral vectors. A major limitation of this approach was the inefficiency of suicide gene delivery. An alternative strategy, in which the suicide genes are physically juxtaposed to the tumor, involves the implantation of encapsulated, genetically modified cells. Cell encapsulation technologies were originally developed for the treatment of acquired and genetic diseases, such as diabetes. In the application of this technology for the treatment of tumors, cells that are genetically modified to overexpress suicide genes are encapsulated and implanted near solid tumors; this process is then followed by systemic prodrug administration. This review discusses the various cells types, suicide genes and prodrugs that have been used in preclinical and clinical trials, as well as the data that have been obtained from these studies. Future improvements for the production of second-generation approaches are also discussed.


PubMed | University of Rostock, Karolinska University Hospital, Heinrich Heine University Düsseldorf, Universitatsklinikum Charite and 2 more.
Type: Journal Article | Journal: Pharmaceutics | Year: 2014

Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.

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