| 1. |
- Cheng, Wing-Shing, et al.
(författare)
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An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer
- 2006
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Ingår i: Cancer Gene Therapy. - 0929-1903 .- 1476-5500. ; 13:1, s. 13-20
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Tidskriftsartikel (refereegranskat)abstract
- The use of conditionally replicating adenoviruses offers an attractive complementary treatment strategy for localized prostate cancer. We have produced a replicating adenovirus, Ad[I/PPT-E1A], where E1A gene expression is controlled by a recombinant regulatory sequence designated PPT. The PPT sequence comprises a PSA enhancer, a PSMA enhancer and a T-cell receptor gamma-chain alternate reading frame protein promoter, and it is shielded from transcriptional interference from adenoviral backbone sequences by an H19 insulator. Ad[I/PPT-E1A] yields prostate-specific E1A protein expression, viral replication and cytolysis in vitro. Furthermore, Ad[I/PPT-E1A] considerably regresses the growth of subcutaneous LNCaP prostate cancer tumors in nude mice. Importantly, the viral replication and cytolytic effect of Ad[I/PPT-E1A] are independent of the testosterone levels in the prostate cancer cells. This may be beneficial in a clinical setting since many prostate cancer patients are treated with androgen withdrawal. In conclusion, Ad[I/PPT-E1A] may prove to be useful in the treatment of localized prostate cancer.
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| 2. |
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| 3. |
- Danielsson, Angelika, 1981-, et al.
(författare)
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The HDAC Inhibitor FK228 Enhances Adenoviral Transgene Expression by a Transduction-Independent Mechanism but Does Not Increase Adenovirus Replication
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2, s. e14700-
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Tidskriftsartikel (refereegranskat)abstract
- The histone deacetylase inhibitor FK228 has previously been shown to enhance adenoviral transgene expression when cells are pre-incubated with the drug. Upregulation of the coxsackie adenovirus receptor (CAR) has been proposed as the main mechanism. In the present study, we found that the highest increase in transgene expression was achieved when non-toxic concentrations of FK228 were added immediately after transduction demonstrating that the main effect by which FK228 enhances transgene expression is transduction independent. FK228 had positive effects both on Ad5 and Ad5/f35 vectors with a variety of transgenes and promoters, indicating that FK228 works mainly by increasing transgene expression at the transcriptional level. In some cases, the effects were dramatic, as demonstrated by an increase in CD40L expression by FK228 from 0.3% to 62% when the murine prostate cancer cell line TRAMP-C2, was transduced with Ad[CD40L]. One unexpected finding was that the transgene expression of an adenoviral vector with the prostate-specific PPT promoter decreased in the human prostate cancer cell line LNCaP when FK228 was administered. This is probably a consequence of phenotypic alteration of LNCaP towards a neuroendocrine phenotype after FK228 treatment. The observations in this study indicate that FK228 enhances adenoviral therapy by a transduction-independent mechanism. Furthermore, since histone deacetylase inhibitors may alter the phenotype of cells, it is important to keep in mind that the activity and specificity of tissue- and tumor-specific promoters may also be affected.
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| 4. |
- Dzojic, Helena, 1978-
(författare)
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Adenovirus-mediated CD40 Ligand Immunotherapy of Prostate and Bladder Cancer
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer immunotherapy aims at reversing the immunosuppressive tumor environment and enhancing anti-tumor immunity. This thesis comprises studies on murine models for prostate (TRAMP-C2) and bladder (MB49) cancer with the aim to explore if the introduction of an adenoviral vector expressing CD40 ligand (AdCD40L) can induce anti-tumor immune responses.We show in subcutaneous mouse models that AdCD40L treatment suppresses tumor growth. Bladder cancer is known to secrete immunosuppressive IL-10 which may inhibit T cell function. We show that introducing AdCD40L into mouse bladder tumors inhibits IL-10 production and reverses immunosuppression. AdCD40L-transduced mouse prostate cancer cells showed caspase activation and reduced cell viability. Vaccination with CD40L-modified prostate cancer cells induces anti-tumor responses and protects mice against rechallenge with native TRAMP-C2 cells. In order to enhance AdCD40L therapy, we explored the possibility of combining it with the histone deacetylase inhibitor FK228, also known as depsipeptide. We show that FK228 upregulates coxsackie and adenovirus receptor expression and thereby enhances adenoviral-mediated CD40L expression in both murine and human prostate cancer cells. Increasing amounts of FK228 or AdCD40L reduces prostate cancer cell viability, while the combined treatment gives at least an additive therapeutic effect. Moreover, we show that AdCD40L transduction of prostate cancer cells induces endogenous CD40 expression and sensitize them for CD40L-mediated therapy.In order to conduct prostate-specific gene therapy, prostate-specific promoters can be used to drive transgene expression. However, there are no reports on prostate-specific promoters that are transcriptionally active in mouse cells. Here we show that by using the two-step transcription activation system (TSTA), we can enhance the activity of a recombinant human promoter sequence and obtain activity in mouse prostate cancer cells as well. This finding paves the way for future studies of prostate-specific gene therapy in immunocompetent mouse models.
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| 5. |
- Dzojic, Helena, et al.
(författare)
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Adenovirus-Mediated CD40 Ligand Therapy Induces Tumor Cell Apoptosis and Systemic Immunity in the TRAMP-C2 Mouse Prostate Cancer Model
- 2006
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 66:8, s. 831-838
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The interaction between CD40 ligand (CD40L) and CD40 on antigen presenting cells is essential for the initiation of antigen-specific T-cell responses, whereas CD40L stimulation of CD40+ tumor cells can induce cellular apoptosis. We investigated the anti-tumor effects induced by CD40L gene transfer into the mouse prostate adenocarcinoma cell line TRAMP-C2, both in vitro and in vivo. METHODS: TRAMP-C2 cells were transduced with an adenoviral vector encoding CD40L (AdCD40L). The induced expression of co-stimulatory molecules and cell viability was analyzed. AdCD40L-transduced TRAMP-C2 cells were used in prophylactic vaccination studies, while therapeutic studies were performed using peritumoral injections of AdCD40L. RESULTS: AdCD40L yielded reduced TRAMP-C2 cell viability and induced apoptosis in vitro. Vaccination with CD40L-expressing TRAMP-C2 cells induced anti-tumor immunity and peritumoral AdCD40L injections induced tumor growth suppression. CONCLUSIONS: Our observations highlight the therapeutic potential of using AdCD40L as a monotherapy or in combination with conventional chemotherapy or novel therapies (e.g., oncolytic viruses). The use of AdCD40L offers an attractive option for future clinical trials.
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| 6. |
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| 7. |
- Dzojic, Helena, et al.
(författare)
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Two-step amplification of the human PPT sequence provides specific gene expression in an immunocompetent murine prostate cancer model
- 2007
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Ingår i: Cancer Gene Therapy. - : Springer Science and Business Media LLC. - 0929-1903 .- 1476-5500. ; 14:3, s. 233-240
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Tidskriftsartikel (refereegranskat)abstract
- The recombinant prostate-specific PPT sequence comprises a prostate-specific antigen enhancer, a PSMA enhancer and a TARP promoter. It is transcriptionally active in human prostate cancer cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer, it has no detectable transcriptional activity. Herein, we describe that the PPT sequence in combination with a two-step transcriptional amplification (TSTA) system becomes active also in murine prostate cancer cells. An adenovirus with TSTA-amplified PPT-controlled expression of the luciferase reporter gene, Ad[PPT/TSTA-Luc], has up to 100-fold higher prostate-specific transcriptional activity than a non-amplified PPT-based adenovirus, Ad[PPT-Luc], in human cells. In addition, Ad[PPT/TSTA-Luc] confers prostate-specific transgene expression in murine cells, with an activity that is approximately 23% of Ad[CMV-Luc] in the transgenic adenocarcinoma of the mouse prostate (TRAMP)-C2 cells. Moreover, to visualize luciferase expression in living mice a charge-coupled device camera was used. Ad[PPT/TSTA-Luc] yielded approximately 30-fold higher transgene expression than Ad[PPT-Luc] in LNCaP tumor xenografts. Importantly, Ad[PPT/TSTA-Luc] also showed activity in murine TRAMP-C2 tumors, whereas Ad[PPT-Luc] activity was undetectable. These results highlight that the recombinant PPT sequence is active in murine prostate cancer cells when augmented by a TSTA system. This finding opens up for preclinical studies with prostate-specific therapeutic gene expression in immunocompetent mice.
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| 8. |
- Leja, Justyna, et al.
(författare)
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A novel chromogranin-A promoter-driven oncolytic adenovirus for midgut carcinoid therapy
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:8, s. 2455-2462
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene. Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases. Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes. Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.
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| 9. |
- Loskog, Angelica, et al.
(författare)
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Adenovirus CD40 Ligand Gene Therapy Counteracts Immune Escape Mechanisms in the Tumor Microenvironment
- 2004
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 172:11, s. 7200-7205
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Tidskriftsartikel (refereegranskat)abstract
- Tumors exhibit immune escape properties that promote their survival. These properties include modulation of Ag presentation, secretion of immunosuppressive factors, resistance to apoptosis, and induction of immune deviation, e.g., shifting from Th1- to Th2-type responses. These escape mechanisms have proven to hamper several immunotherapeutic strategies, and efforts need to be taken to revert this situation. We have studied the immunological effects of introducing CD40 ligand (CD40L), a potent dendritic cell activation molecule, into the tumor micromilieu by adenoviral gene transfer. For this purpose, a murine bladder cancer model (MB49) was used in C57BL/6 mice. The MB49 cells are known to induce IL-10 in the tumor environment. IL-10 potently inhibits the maturation of dendritic cells and thereby also the activation of CTLs. In this paper we show that CD40L immunogene therapy suppresses IL-10 and TGF-beta production (2-fold decrease) and induces a typical Th1-type response in the tumor area (200-fold increase in IL-12 production). The antitumor responses obtained were MB49 cell specific, and the cytotoxicity of the stimulated CD8(+) cells could be blocked by IL-10. Adenovirus CD40L therapy was capable of regressing small tumors (five of six animals were tumor free) and inhibiting the progression of larger tumors even in the presence of other escape mechanisms, such as apoptosis resistance. Furthermore, CD40L-transduced MB49 cells promoted the maturation of dendritic cells (2-fold increase in IL-12) independently of IL-10. Our results argue for using adenovirus CD40L gene transfer, alone or in combination with other modalities, for the treatment of Th2-dominated tumors.
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