Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A replication competent foamy virus derived retroviral vector expressing suicide genes has been constructed and characterized in vitro. Here we used vectors expressing the purine nucleoside phosphorylase (FOV-7/pnp), the nitroreductase (FOV-7/ntr), or the thymidine kinase (FOV-7/tk) suicide gene in an in vivo athymic (nude) mice/human glioblastoma tumor model. Gliomas were induced by subcutanous injection of U87 tumor cells. The virus vector was injected when the tumor became visible. Mice with vector virus-injected tumors were treated with the respective prodrug. The treatment resulted in significant inhibition of tumor growth. Surprisingly, in mice with vector virus-injected tumors without prodrug treatment a similar suppression of tumor growth was observed. In 65% (pnp vector), 75% (ntr vector) and 37% (tk vector) of these mice the tumors stopped growing or vanished and the animals remained tumor free for the 25 weeks of the experiment, whereas all mice of the control groups had to be killed because of the tumor growth. In control experiments, the suppression of tumor growth could also be observed when wild-type foamy virus was injected instead of the suicide gene-transducing vectors. Similar results were obtained using the nude mice/G59 human glioblastoma tumor model. In conclusion, the experiments demonstrate an oncolytic activity of foamy virus replication in a nude-mice glioblastoma xenograft tumor model. The analysis of vector virus DNA by PCR revealed that the vector persisted in different organs of the animals irrespective of the use of a prodrug or the elimination of a tumor.
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PMID:Experimental therapy of allogeneic solid tumors induced in athymic mice with suicide gene-transducing replication-competent foamy virus vectors. 1590 57

Transduced deoxyribonucleoside kinases (dNK) can be used to kill recipient cells in combination with nucleoside prodrugs. The Drosophila melanogaster multisubstrate dNK (Dm-dNK) displays a superior turnover rate and has a great plasticity regarding its substrates. We used directed evolution to create Dm-dNK mutants with increased specificity for several nucleoside analogs (NAs) used as anticancer or antiviral drugs. Four mutants were characterized for the ability to sensitize Escherichia coli toward analogs and for their substrate specificity and kinetic parameters. The mutants had a reduced ability to phosphorylate pyrimidines, while the ability to phosphorylate purine analogs was relatively similar to the wild-type enzyme. We selected two mutants, for expression in the osteosarcoma 143B, the glioblastoma U-87M-G and the breast cancer MCF7 cell lines. The sensitivities of the transduced cell lines in the presence of the NAs fludarabine (F-AraA), cladribine (CdA), vidarabine and cytarabine were compared to the parental cell lines. The sensitivity of 143B cells was increased by 470-fold in the presence of CdA and of U-87M-G cells by 435-fold in the presence of F-AraA. We also show that a choice of the selection and screening system plays a crucial role when optimizing suicide genes by directed evolution.
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PMID:Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs. 1758 98

Suicide cancer gene therapy with retroviral vector-producing cells was in the way of an adjuvant to the surgical resection of recurrent glioblastoma, although any benefit appeared to be marginal. It is likely that this therapeutic approach may have better outcomes if the vectors and transgenes are delivered more efficiently to the tumor cells. We have shown previously that tumor cells engineered by adenovirus-retrovirus hybrid vectors to produce retroviral progeny destroy satellite tumor cells. Whether the systemic delivery of vector-producing cells can effectively treat aggressive tumors remains to be determined. Effective retroviral vector delivery vehicles may be multipotent mesenchymal stromal cells (MSCs), which have been shown to home to tumor cells in vivo and deliver cancer-killing gene or immune products with minimal host rejection. Therefore, it may be possible to transduce tumors with recombinant progeny vectors delivered by MSCs. This may be particularly suitable for treating diffuse cancers like glioblastoma multiforme. While this strategy remains to be tested in various orthotopic or metastatic tumor models, it has the potential to greatly improve the outcome of suicide gene therapy.
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PMID:Vector-producing tumor-tracking multipotent mesenchymal stromal cells for suicide cancer gene therapy. 1798 76

Oncolytic virotherapy represents an emerging field with tremendous promise for harnessing the replicative capabilities of viruses against rapidly proliferating cancer cells. Among the different replicating virus technologies being tested, replication-competent retrovirus (RCR) vectors based on murine leukemia virus (MLV) exhibit unique characteristics. MLV exhibits intrinsic tumor selectivity due to its inability to infect quiescent cells, and can achieve highly selective and stable gene transfer throughout entire solid tumors in vivo at efficiencies of up to >99%, even after initial inoculation at MOIs as low as 0.01. RCR vectors with suicide genes mediate synchronized cell killing after prodrug administration, and due to their ability to undergo stable integration, residual cancer cells serve as a reservoir for long-term viral persistence even as they migrate to new sites, enabling multiple cycles of prodrug to achieve prolonged survival benefit. Further testing in various tumor models, new vector targeting and delivery strategies, and development of GMP manufacturing, are being pursued through a multi-national consortium, and preparations are now being undertaken for clinical trials using RCR vectors in glioblastoma.
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PMID:Replication-competent retrovirus vectors for cancer gene therapy. 1798 78

Development of antineoplastic gene therapies is impaired by a paucity of transcription control elements with efficient, cancer cell-specific activity. We investigated the utility of promoter (AChP) and 5'-distal enhancer (ACE66) elements from the platelet-derived growth factor-A (PDGF-A) gene, which are hyperactive in many human cancers. Efficacy of these elements was tested in multiple tumor cell lines, both in cell culture and as tumor explants in athymic nude mice. Plasmid and viral vectors were constructed with the AChP promoter alone or in fusion with three copies of the ACE66 enhancer for expression of the prototype suicide gene, thymidine kinase (TK). ACE/AChP and AChP cassettes elicited ganciclovir (GCV)-induced cytotoxicity in multiple tumor cell lines. The ACE enhancer element also exhibited synergism with placental and liver-specific promoter elements. An adenovirus containing the AChP-TK cassette produced striking increases in GCV sensitivity in cultured tumor cell lines, as well as GCV-induced regression of U87 MG glioblastoma explants in vivo. TK expression was distributed throughout tumors receiving the therapeutic virus, whereas TdT-mediated dUTP nick end labeling (TUNEL) analysis revealed numerous regions undergoing apoptosis. Vascularization and reticulin fiber networks were less pronounced in virus-GCV-treated tumors, suggesting that both primary and stromal cell types may have been targeted. These studies provide proof-of-principle for utility of the PDGF-A promoter and ACE66 enhancer in antineoplastic gene therapy for a diverse group of human cancers.
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PMID:PDGF-A promoter and enhancer elements provide efficient and selective antineoplastic gene therapy in multiple cancer types. 1898 53

Suicide gene therapy with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) is notable for producing multi-log cytotoxicity in a unique pattern of delayed cytotoxicity in S-phase. As hydroxyurea, a ribonucleotide reductase inhibitor that activates mismatch repair, can increase sensitivity to GCV, we evaluated the role of MLH1, an essential mismatch repair protein, in GCV cytotoxicity. Using HCT116TK (HSV-TK-expressing) colon carcinoma cells that express or lack MLH1, cell-survival studies demonstrated greater GCV sensitivity in the MLH1-deficient cells, primarily at high concentrations. This could not be explained by differences in GCV metabolism, as the less sensitive MLH1-expresssing cells accumulated more GCV triphosphate and incorporated more of the analog into DNA. SiRNA suppression of MLH1 in U251 glioblastoma or SW480 colon carcinoma cells also enhanced sensitivity to high concentrations of GCV. Studies in a pa nel of yeast deletion mutants confirmed the results with MLH1, and further suggested a role for homologous recombination repair and several cell-cycle checkpoint proteins in GCV cytotoxicity. These data suggest that MLH1 can prevent cytotoxicity with GCV. Targeting mismatch repair-deficient tumors may increase efficacy of this suicide gene therapy approach to cancer treatment.
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PMID:MLH1 deficiency enhances tumor cell sensitivity to ganciclovir. 1930 Apr 72

Previously we have reported adipose-tissue derived human mesenchymal stem cells (AT-MSC) as cellular delivery vehicles for tumor-targeted cancer gene therapy. In this report we aimed to determine whether Herpes simplex virus - thymidine kinase (HSV-tk) expressing AT-MSC (TK-MSC) could exert cytotoxic effect on tumor cells upon treatment with prodrug ganciclovir (GCV). Direct co-cultures of human glioblastoma cells 8-MG-BA, 42-MG-BA and U-118 MG with TK-MSC/GCV resulted in substantial viability decrease in vitro. This therapeutic paradigm was most efficient against 8-MG-BA glioblastoma cells exhibiting cytotoxicity (>50%) in the presence of TK-MSC and 0.1microM GCV. Rapid apoptosis induction in three glioblastoma cell lines and TK-MSC demonstrated both bystander cytotoxic effect on tumor cells and GCV conversion-mediated suicide effect on TK-MSC. Furthermore, we were able to demonstrate formation of gap junctions between AT-MSC and human glioblastoma cells as a mechanism contributing to bystander cytotoxicity. Inability of human HeLa and MCF7 to form gap junctions with AT-MSC rendered these cell refractory to the TK-MSC/GCV mediated cytotoxicity. Gap junction intercellular communication (GJIC) capability of AT-MSC with tumor cells further supports the exploitation of mesenchymal stem cells for approaches relying on the bystander effect. Biological consequences of these capabilities remain to be further explored.
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PMID:HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. 1976 92

Transcriptional targeting using a tissue-specific cellular promoter is proving to be a powerful means for restricting transgene expression in targeted tissues. In the context of cancer suicide gene therapy, this approach may lead to cytotoxic effects in both cancer and nontarget normal cells. Considering microRNA (miRNA) function in post-transcriptional regulation of gene expression, we have developed a viral vector platform combining cellular promoter-based transcriptional targeting with miRNA regulation for a glioma suicide gene therapy in the mouse brain. The therapy employed, in a single baculoviral vector, a glial fibrillary acidic protein (GFAP) gene promoter and the repeated target sequences of three miRNAs that are enriched in astrocytes but downregulated in glioblastoma cells to control the expression of the herpes simplex virus thymidine kinase (HSVtk) gene. This resulted in significantly improved in vivo selectivity over the use of a control vector without miRNA regulation, enabling effective elimination of human glioma xenografts while producing negligible toxic effects on normal astrocytes. Thus, incorporating miRNA regulation into a transcriptional targeting vector adds an extra layer of security to prevent off-target transgene expression and should be useful for the development of gene delivery vectors with high targeting specificity for cancer therapy.
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PMID:Combinatorial control of suicide gene expression by tissue-specific promoter and microRNA regulation for cancer therapy. 1980 2

Side populations of glioblastoma cells are resistant to chemotherapy basically due to ABCG2-mediated efflux of small-molecule drugs. The herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy system is one of the best-characterized strategies for malignant tumors including glioblastoma. Since this system involves a small-molecule drug ganciclovir, we wonder if glioblastoma side population cells are able to "pump out" ganciclovir and thus resistant to this suicide gene therapy. By 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, we found that side populations are more resistant to this system than non-side populations. By flow cytometry and competition assay, we found that ganciclovir is a substrate for ABCG2.
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PMID:Side populations of glioblastoma cells are less sensitive to HSV-TK/GCV suicide gene therapy system than the non-side population. 2013 58

The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.
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PMID:Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy. 2015 39


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