Retrovirus-mediated gene transfer in cancer therapy
ABSTRACT Retroviral vectors are one of the most promising systems for the transfer and the expression of therapeutic genes in human gene therapy protocols. This review will focus both on the advantages and intricacies of retroviral vectors themselves as well as on the application of these vector systems in experimental and clinical cancer therapy protocols. Therefore, the retrovirus life cycle and the general features of retroviral vectors, including possible targeting strategies with retroviral vectors, are overviewed. These topics are followed by the presentation of genes with emphasis on their potential as tools in somatic cell cancer therapy (cytokines, lymphokines, colony-stimulating growth factors, suppressor genes, antisense oncogenes, suicide genes). Finally, a prospect on the application of retroviral vectors will be described.
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ABSTRACT: Herpes simplex virus (HSV)-based vectors have favorable biologic features for gene therapy of leukemia and lymphoma. These include high transduction efficiency, ability to infect postmitotic cells, and large packaging capacity. The usefulness of HSV amplicon vectors for the transduction of primary human B-cell chronic lymphocytic leukemia (CLL) was explored. Vectors were constructed encoding beta-galactosidase (LacZ), CD80 (B7.1), or CD154 (CD40L) and were packaged using either a standard helper virus (HSVlac, HSVB7.1, and HSVCD40L) or a helper virus-free method (hf-HSVlac, hf-HSVB7.1, and hf-HSVCD40L). Both helper-containing and helper-free vector stocks were studied for their ability to transduce CLL cells, up-regulate costimulatory molecules, stimulate allogeneic T-cell proliferation in a mixed lymphocyte tumor reaction, and generate autologous cytotoxic T lymphocytes (CTLs). Although helper-containing and helper-free amplicon stocks were equivalent in their ability to transduce CLL cells, a vigorous T-cell proliferative response was obtained using cells transduced with hf-HSVB7.1 but not with HSVB7.1. CLL cells transduced with either HSVCD40L or hf-HSVCD40L were compared for their ability to up-regulate resident B7.1 and to function as T-cell stimulators. Significantly enhanced B7.1 expression in response to CD40L was observed using hf-HSVCD40L but not with HSVCD40L. CLL cells transduced with hf-HSVCD40L were also more effective at stimulating T-cell proliferation than those transduced with HSVCD40L stocks and were successful in stimulating autologous CTL activity. It is concluded that HSV amplicons are efficient vectors for gene therapy of hematologic malignancies and that helper virus-free HSV amplicon preparations are better suited for immunotherapy.Blood 08/2001; 98(2):287-95. · 9.06 Impact Factor
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ABSTRACT: Retrovirus (RV) has been one of the earliest recombinant vectors to be investigated in the context of cancer gene therapy. Experiments in cell culture and in animal brain tumor models have demonstrated the feasibility of RV mediated gene transduction and killing of glioma cells by toxicity generating transgenes. Phase I and II clinical studies in patients with recurrent malignant glioma have shown a favorable safety profile and some efficacy of RV mediated gene therapy. On the other hand, a prospective randomized phase III clinical study of RV gene therapy in primary malignant glioma failed to demonstrate significant extension of the progression-free or overall survival times in RV treated patients. The failure of this RV gene therapy study may be due to the low tumor cell transduction rate observed in vivo. The biological effects of the treatment may also heavily depend on the choice of transgene/prodrug system and on the vector delivery methods. Retrovirus clinical trials in malignant glioma have nevertheless produced a substantial amount of data and have contributed toward the identification of serious shortcomings of the non-replicating virus vector gene therapy strategy. Novel types of therapeutic virus vector systems are currently being designed and new clinical protocols are being created based on the lessons learned from the RV gene therapy trials in patients with malignant brain tumors.Journal of Neuro-Oncology 01/2004; 65(3):227-36. · 3.12 Impact Factor
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ABSTRACT: To evaluate the efficacy and safety of empiric transcatheter arterial embolization (TAE) for patients with massive bleeding from duodenal ulcers. During January 2000 and December 2009, 59 patients with duodenal ulcer bleeding in whom TAE was attempted after endoscopic therapy failed were retrospectively analyzed. The patients were divided into empiric TAE (n = 36) and identifiable TAE (n = 23) groups according to angiographic findings with or without identification of the bleeding sites. The technical and clinical success rate, recurrent bleeding rate, procedure-related complications, and clinical outcomes were evaluated. The technical and clinical success rates of TAE were 100% and 83%. The recurrent bleeding rate, clinical success, duodenal stenosis, and 30-day mortality after TAE were not significantly different between the empiric and identifiable TAE groups. A high rate of technical and clinical success was obtained with empiric TAE comparable to identifiable TAE in patients with massive bleeding from duodenal ulcers. There were no severe complications. Empiric TAE is an effective and safe method when a bleeding site cannot determined by angiography.Journal of vascular and interventional radiology: JVIR 05/2011; 22(7):911-6. · 1.81 Impact Factor