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Results for “Genes, Transgenic, Suicide”

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At least 19 recordsLinked to original sources
PubMed2004

Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene.

Transgenic mice expressing an inducible suicide gene, which allows systemic and reversible elimination of macrophages, were developed. A macrophage-specific c-fms promoter was used to express enhanced green fluorescent protein and a drug-inducible suicide gene that leads to Fas-mediated apoptosis in resting and cycling cells of the macrophage lineage. Transgenic mice were fertile, of normal weight, and showed no abnormal phenotype before drug exposure. The transgene was expressed constitutively in macrophages and dendritic cells (DC) but not significantly in T cells or B cells. Induction of the suicide gene led to depletion of 70-95% of macrophages and DC in nearly all tissues examined. Depletion reduced the ability to clear bacteria from the blood and led to increased bacterial growth in the liver. Depleted mice displayed several abnormalities, including splenomegaly, lymphadenopathy, thymic atrophy, extramedullary hematopoiesis, and development of peritoneal adhesions. This new, transgenic line will be useful in investigating the role of macrophages and DC.

Animals↗
PubMed2005

Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation.

In allogeneic hematopoietic cell transplantation (allo-HCT), donor lymphocytes play a central therapeutic role in both GvL and immune reconstitution. However, the full exploitation of these therapeutic properties is limited by the occurrence of GvHD. Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GvHD. The genetic engineering of donor lymphocytes with the herpes simplex virus-thymidine kinase (HSV-TK) suicide gene confers the ability to modulate GvHD by invivo ganciclovir-induced elimination of the transduced cells. The suicide-gene strategy has applications in both donor lymphocyte infusion (DLI) for disease relapse and in add-back infusions after T-cell depleted allo-HCT. TK cell DLI resulted in anti-tumor activity in a relevant proportion of treated patients. Haplo-identical stem cell transplantation (haplo-HCT) is a promising therapeutic option for patients with high risk hematologic malignancies lacking an HLA-matched donor. However, the profound T-cell depletion required to overcome the risk of lethal GvHD has been associated with a marked delayed T-cell recovery with a prolonged risk of post-transplant viral, fungal and other opportunistic infections. TK cell add-backs efficiently promote early immune reconstitution after haplo-HCT and prevent disease relapse, providing a unique tool for the control of GvHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allo-HCT.

Animals↗
PubMed2003

Inducible liver injury in the transgenic rat by expressing liver-specific suicide gene.

Suicide gene expression in specific tissue of transgenic animals has been used for cell-specific ablation. To examine the influence of hepatocyte removal, we produced the herpes simplex virus thymidine kinase (HSVtk) transgenic rat, whose gene was regulated by an albumin enhancer promoter. The liver presence of HSVtk was demonstrated in one line of the transgenic rats. We injected ganciclovir (GCV, 50mg/kg) into the rat on alternate days. After 28 days of GCV administration, liver tissues, and blood of the rats were collected. The histological investigation revealed infiltration of T cells, macrophages, granulocytes/neutrophils, and hepatocyte cell death. The biochemistry analysis demonstrated elevated levels of AST, ALT, and total bilirubin in transgenic rat. In conclusion, the transgenic rat with expressed albumin-specific HSVtk developed experimental hepatitis with administration of GCV, and will be a useful model to facilitate the evaluation of drug effects for clinical control of liver disease.

Animals↗
PubMed2004

Activation of stress-responsive promoters by ionizing radiation for deployment in targeted gene therapy.

Radiotherapy is one of the principal modalities of cancer treatment, but the delivery of a curative dose of ionizing radiation (IR) to the tumour is frequently limited by the need to protect the normal tissues within the irradiated area from radiation damage. This problem could be circumvented if tumour cells could be selectively sensitized to killing by IR. One way to achieve this goal would be to transduce the tumour cells with expression vectors carrying toxin genes under the control of promoters that are inactive unless induced by IR. For this approach to be successful, two parameters must be met: (i) the expression vector has to be delivered to the tumour or its immediate vicinity (e.g. its vasculature) and (ii) the promoter driving the expression of the toxin gene has to have negligible basal activity, yet has to be activated by clinically-achievable doses of IR. Several vectors that fulfil these criteria are currently reaching clinical trials. In this review, we examine the response of mammalian cells to IR, and the current status of radiation-induced suicide gene therapy that is dependent on this response.

Apoptosis↗
PubMed2003

Gene therapy for lung cancer.

Lung cancer continues to be the largest killer of Americans due to cancer. Although progress has been made, with advances in chemotherapy, the majority of patients diagnosed with lung cancer ultimately succumb to the disease. A better understanding of the molecular pathogenesis of lung cancer is demonstrating how alterations in oncogenes and tumor suppressor genes control lung cancer initiation, growth, and survival. In this article, attempts to target molecular alterations in lung cancer using gene therapy techniques are reviewed. These include introducing suicide genes into tumor cells, replacement of defective tumor suppressor genes, inactivating oncogenes, and immunotherapy-based approaches using gene therapy technology. The major barrier for these techniques continues to be the inability to specifically target tumor cells while sparing normal cells. Nonetheless, these approaches are likely to yield important biologic and clinical data which will further the progress of lung cancer treatment.

Genes, Transgenic, Suicide↗
PubMed2006

Cancer-specific targeting of an adenovirus-delivered herpes simplex virus thymidine kinase suicide gene using translational control.

Two technical hurdles, gene delivery and target specificity, have hindered the development of effective cancer gene therapies. In order to circumvent the problem of tumor specificity, the suicide gene, HSV-1 thymidine kinase (HSV-Tk), was modified with a complex 5' upstream-untranslated region (5'-UTR) that limits efficient translation to cells expressing high levels of the translation initiation factor, eIF4E. Since previous studies have shown that most tumor cells express elevated levels of eIF4E, tumor-specific gene delivery was optimized by incorporation of the 5'-UTR-modified suicide gene (HSV-UTk) into an adenovirus vector (Ad-CMV-UTk). The efficacy of this novel approach of targeting suicide gene expression and limiting cytotoxicity by means of translational restriction was tested in vitro with the use of the human breast cancer cell lines (MCF-7, MDA-MB435, and ZR-75-1). As controls, normal MCF10A, HMEC, and HMSC cell lines that express relatively low levels of eIF4E were used. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to quantify HSV-Tk mRNA for cells infected with Ad-CMV-UTk as well as with Ad-CMV-Tk (a control adenovirus in which HSV-Tk is not regulated at the level of translation). Translation of HSV-Tk in the Ad-infected cells was measured by Western blot analysis. In addition, cytotoxicity was determined following treatment with the pro-drug ganciclovir (GCV) using an MTT viability assay. Finally, microPET imaging was used to assess cancer cell-specific expression of HSV-Tk and expression in normal tissues in vivo after intraperitoneal injection of Ad-CMV-Tk or Ad-CMV-UTk. These data collectively showed enhanced cancer cell-specific gene expression and reduced normal tissue gene expression for the Ad-HSV-UTk compared to the Ad-CMV-Tk, leading to increased cancer cell-enhanced GCV cytotoxicity. These results indicate that translational targeting of suicide gene expression in tumor cells in vitro and in vivo is effective and may provide a platform for enhanced cancer gene therapy specificity.

Adenoviruses, Human↗
PubMed2006

Gene therapy for gastric cancer: is it promising?

Gastric cancer is one of the most common tumors worldwide. The therapeutic outcome of conventional therapies is inefficient. Thus, new therapeutic strategies are urgently needed. Gene therapy is a promising molecular alternative in the treatment of gastric cancer, including the replacement of defective tumor suppressor genes, the inactivation of oncogenes, the introduction of suicide genes, genetic immunotherapy, anti-angiogenetic gene therapy, and virotherapy. Improved molecular biological techniques and a better understanding of gastric carcinogenesis have allowed us to validate a variety of genes as molecular targets for gene therapy. This review provides an update of the new developments in cancer gene therapy, new principles, techniques, strategies and vector systems, and shows how they may be applied in the treatment of gastric cancer.

Angiogenesis Inhibitors↗
PubMed2005

[Prostate cancer gene therapy].

With the advance in genetic engineering, tumor biology and immunology, gene therapy has been recognized as a promising new treatment option for cancer including prostate cancer. Several clinical trials of prostate cancer gene therapy are currently underway, using therapeutic genes which include suicide genes, immunomodulatory genes, tumor suppressor genes and anti-oncogenes. Although the gene therapy for prostate cancer as a clinical alternative is still early stage which requires several technological breakthrough, some information obtained from clinical trial indicates full potential of prostate cancer gene therapy. Concordant progress both in the basic research and gene therapy technology will make prostate cancer gene therapy ready for wide-scale of practice in the future. In this report, general concept and current progress in prostate cancer gene therapy are summarized.

Adenoviridae↗
PubMed2006

[Gene therapy for relapsed breast cancer].

Gene therapy for advanced breast cancer is anticipated to be a useful therapeutic approach. Strategies in ongoing clinical protocols can be divided into four groups: (1) suppression of oncogenes or transfer of tumor-suppressor genes: (2) enhancement of immunological response: (3) transfer of suicide genes: (4) protection of bone marrow using drug resistance genes. We have started a clinical study of multidrug resistance (MDR1) gene therapy. Patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT) with MDR1-transduced hematopoietic cells, and then were treated with docetaxel. Three patients have been treated so far, and in vivo enrichment of MDR1-transduced cells with docetaxel treatment has been seen. There has been no apparent adverse effect from the MDR1 gene transfer.

Breast Neoplasms↗
PubMed2004

Gene therapy for thyroid cancer.

Thyroid carcinomas are suitable targets for gene therapy because they can be highly lethal on one hand, while being susceptible to specific tumour targeting on the other hand. Several gene therapy modalities have been evaluated so far in experimental models of thyroid cancer, including tumour suppressor gene replacement, oncogene inhibition, suicide gene therapy, immunotherapy, antiangiogenesis, and viral oncolysis. All of these strategies have shown promising results, but clinical studies are lacking. Based on the clinical experience achieved in a pilot study in patients with advanced thyroid cancer and on clinical results in other types of solid cancer, it is suggested that combined gene therapy approaches, as well as multimodality therapeutic regimens, including gene therapy and conventional treatments, should be pursued to achieve clinically significant results.

Animals↗
PubMed2005

Replacement and suicide gene therapy for targeted treatment of lung cancer.

Lung cancer is the leading cause of cancer-related death in the developed world; consequently, novel therapeutic strategies are in high demand. A major problem with the present treatment modalities is the lack of tumor specificity giving rise to dose-limiting toxicity and side effects. Gene therapy constitutes an experimental approach gaining increased attention as a putative future cancer therapeutic strategy. Using this strategy, cancer cytotoxicity can be obtained by replacing mutated genes with functional analogues or introducing a suicide gene into the malignant cells. Insight into the molecular biology of cancer cells has identified a number of regulatory gene sequences, which can be used to selectively activate the therapeutic gene specifically in cancer cells, thereby reducing nonspecific toxicity. Although further improvements are necessary, recent encouraging results have shown promise for future clinical application of gene therapy. This article presents an update on the experimental and clinical results obtained within the field of lung cancer gene therapy, concentrating on strategies to specifically activate expression of the therapeutic gene in cancer cells. Furthermore, status of the development of delivery vector constructs for lung cancer gene therapy will be presented.

Animals↗
PubMedDate not supplied

Gene therapy for lung cancer: practice and promise.

Gene therapy has emerged as an exciting and promising strategy of cancer therapy. Improved molecular biology techniques and a greater understanding of the mechanisms involved in lung cancer pathogenesis allowed a variety of genes to be validated as molecular targets for gene therapy. A variety of gene therapy strategy have been explored in the pre-clinical research. These include replacement of defective tumor suppressor genes, inactivating oncogenes, introducing suicide genes, immunogenic therapy, and antiangiogenesis-based approach. Clinical trials of gene therapy for lung cancer showed the feasibility of delivering a variety of agent as well as highlighted problems with the delivery of therapeutic constructs. Although some may consider the initial results of these novel therapies to be disappointing, they underscore the complexity of these approaches and the likelihood that these approaches will be effective only when used in a coordinated fashion in the proper clinical context. This review provides an update on our current understanding of lung cancer biology and examines several important issues in cancer gene therapy. In addition, recent results of clinical trials of gene therapy for lung cancer are presented.

Apoptosis↗
PubMed2005

Genetic and physiological characterization of 23S rRNA and ftsJ mutants of Borrelia burgdorferi isolated by mariner transposition.

Borrelia burgdorferi contains one 16S rRNA gene and two tandem sets of 23S and 5S rRNA genes located in a single chromosomal region. This unusual rRNA gene organization has been speculated to be involved in the slow growth of this organism. Because we were repeatedly unable to isolate a 23S ribosomal mutant in B. burgdorferi by allelic exchange, we developed a transposition mutagenesis system for this bacterium. To this end, Himar1 transposase is expressed in B. burgdorferi from a resident plasmid containing an erythromycin resistance marker, and this strain is then electroporated with suicide plasmids containing mariner transposons and kanamycin resistance genes expressible in B. burgdorferi. This system permitted us to generate hundreds of erythromycin/kanamycin-resistant B. burgdorferi clones with each of three suicide plasmids. DNA sequencing of several kanamycin-resistant clones generated with one of the suicide plasmids showed stable and random insertion of the transposon into the B. burgdorferi chromosomal and plasmid genome. One mutant was inactivated in rrlA (23S rRNA), another in ftsJ (rrmJ). rrlA disruption had no effect on growth rate under a wide range of culture conditions, but disruption of ftsJ interfered significantly with growth rate and bacterial morphology. These data show it is possible to isolate random and stable B. burgdorferi transposition mutants for physiological analysis of this pathogenic spirochete.

Bacterial Proteins↗
PubMed2004

Midkine promoter can mediate transcriptional activation of a fused suicide gene in a broader range of human breast cancer compared with c-erbB-2 promoter.

We examined the expression level of the midkine (MK) and c-erbB-2 genes in both tumorous and matched nontumorous specimens from 18 patients with breast cancer. Expression of the MK and c-erbB-2 genes in nontumorous regions was relatively low, and the expression levels of both genes were not markedly different among the nontumorous samples. In contrast, the expression of the MK and c-erbB-2 genes in tumorous specimens was upregulated in 18 and 6 specimens, respectively. Regulatory regions of the MK gene were able to activate a reporter gene to a similar degree as those of the c-erbB-2 gene in the human breast cancer cell lines tested. Transfection of breast cancer cells with either the MK promoter- or the c-erbB-2 promoter-linked herpes simplex virus thymidine kinase gene increased their sensitivity to the prodrug ganciclovir. These data showed that the MK promoter activated a therapeutic gene in a wider range of human breast cancer than the c-erbB-2 promoter and suggest that MK promoter-mediated gene therapy is potentially more favorable in clinical settings.

Adult↗
PubMed2006

Gene transfer approaches for gynecological diseases.

Gene transfer presents a potentially useful approach for the treatment of diseases refractory to conventional therapies. Various preclinical and clinical strategies have been explored for treatment of gynecological diseases. Given the direst need for novel treatments, much of the work has been performed with gynecological cancers and ovarian cancer in particular. Although the safety of many approaches has been demonstrated in early phase clinical trials, efficacy has been mostly limited so far. Major challenges include improving gene transfer vectors for enhanced and selective delivery and achieving effective penetration and spread within advanced and complex tumor masses. This review will focus on current and developmental gene transfer applications for gynecological diseases.

Adenoviridae↗
PubMed2003

Lung cancer vaccines and gene therapy.

A number of cancer vaccine and gene therapy approaches are being evaluated in patients with lung cancer. Cancer vaccine strategies include GM-CSF gene-modified cancer cells, liposomal MUC1 peptide, anti-idiotype antibody targeting GD3, Mage-3 peptide, and mutant p53 pulsed dendritic cells among others. Preliminary human trials have demonstrated immune responses as well as tumor regression in late stage disease. The largest human gene therapy experience in lung cancer is with intratumoral gene replacement therapy, predominantly with p53, but such approaches are limited to locoregional disease control. Earlier stage gene therapy programs targeting the immune system or tumor vasculature hold promise as systemic therapies for treatment of advanced, disseminated disease.

Angiogenesis Inhibitors↗
PubMed2005

Gene therapy for lung cancer.

Over the past three decades, the molecular biology of lung cancer has been progressively delineated. Concurrently, gene therapy techniques have been developed that allow targeting or replacement of dysfunctional genes in cancer cells, such as activated tumor-promoting oncogenes, inactivated tumor-suppressing, or apoptosis-promoting genes. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of gene therapy.

Carcinoma, Non-Small-Cell Lung↗