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Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
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2005 (English)In: Laboratory Animals. Journal of the Laboratory Animal Science Association, ISSN 0023-6772, Vol. 39, no 4, 384-393 p.Article in journal (Refereed) Published
Abstract [en]

Bladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting. The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate. Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.

Place, publisher, year, edition, pages
2005. Vol. 39, no 4, 384-393 p.
Keyword [en]
Adenoviridae/genetics, Animals, Antigens; Neoplasm/biosynthesis/genetics, Benzenesulfonates/pharmacology, Bladder Neoplasms/genetics/metabolism/pathology/*therapy, Blotting; Western, Cell Line; Tumor, Female, Gene Therapy/*methods, Genetic Vectors, H-Y Antigen/biosynthesis/genetics, Lung Neoplasms/secondary, Male, Mice, Mice; Inbred C57BL, RNA; Neoplasm/chemistry/genetics, Research Support; Non-U.S. Gov't, Reverse Transcriptase Polymerase Chain Reaction, Specific Pathogen-Free Organisms, Transduction; Genetic/methods, Tumor Markers; Biological/metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94282DOI: 10.1258/002367705774286475PubMedID: 16197705OAI: oai:DiVA.org:uu-94282DiVA: diva2:168081
Available from: 2006-04-11 Created: 2006-04-11 Last updated: 2010-09-15Bibliographically approved
In thesis
1. Cancer Immunotherapy: A Preclinical Study of Urinary Bladder Cancer
Open this publication in new window or tab >>Cancer Immunotherapy: A Preclinical Study of Urinary Bladder Cancer
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacillus Calmette Guérin (BCG), or attenuated Mycobacterium bovis, is the gold standard of immunotherapy in the clinic to treat superficial bladder cancer. However, setbacks remain due to a high recurrence rate, side effects, and BCG-refractory disease. In this thesis, we explored the use of novel immunotherapeutic agents such as CpG oligodeoxynucleotides (CpG ODNs) or synthetic ODNs containing unmethylated CpG dinucleotides. Since unmethylated CpG motifs are predominant in bacterial but not vertebrate DNA, they function as a “danger signal” leading to a potent immune response.

To be able to test various immunotherapeutic agents, we optimized subcutaneous (s.c.), metastatic, and orthotopic models using the murine bladder-49 (MB49) cancer cell line. In the orthotopic model, we show that poly-L-lysine promotes MB49 attachment to the bladder leading to 100% tumor take. In addition, Clorpactin (sodium oxychlorosene) potently enhances adenoviral transduction in the bladder.

Utilizing the MB49 model, we compare CpG ODNs with BCG and demonstrate the increased efficacy of CpG ODNs which could cure both s.c. and aggressive orthotopic bladder cancer. In our model, type B ODNs were most optimal and the antitumor response required T cells in order to induce regression and tumor-specific immunity. We also combined CpG ODNs with adenoviral vectors (Ad) expressing the immunostimulatory molecules CD40L, TRANCE, lymphotactin, IL2 or IL15. However, we show that CpG ODNs are effective as a monotherapy and adenoviral vectors did not enhance the effect.

AdCD40L was also used to genetically modify human dendritic cells (DCs). AdCD40L-transduced DCs not only had a higher and prolonged expression of the Th1 cytokine IL12 compared to TNFα-matured DCs, but CD40L-activated DCs could also resist the suppressive effects of IL10 and TGFβ. Since TNFα is commonly used in clinical DC vaccination protocols and because tumors often secrete immunosuppressive cytokines, these data have important implications for optimizing cancer immunotherapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 134
Keyword
Medicine, immunotherapy, bladder carcinoma, cancer, CpG ODNs, Adenoviral vector, CD40L, TRANCE, Lymphotactin, IL2, IL15, Medicin
Identifiers
urn:nbn:se:uu:diva-6761 (URN)91-554-6525-0 (ISBN)
Public defence
2006-05-05, Rudbeck Hall, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, Uppsala, 09:15
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Available from: 2006-04-11 Created: 2006-04-11Bibliographically approved

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Alimohammadi, MohammedMalmström, Per-UnoTötterman, Thomas H.

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