UMLS:C0017636 - FACTA Search

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy for malignant glioma with the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is already in the stage of clinical trials, but still needs major improvement to achieve greater clinical efficacy. The aim of this study was to determine whether combining HSV-tk/GCV gene therapy with temozolomide (TMZ), an alkylating drug clinically proven to be efficient in recurrent high-grade gliomas, would result in enhanced antitumor effect in malignant glioma in culture and in vivo. Human U87MG glioblastoma (GBM) cells with or without expression of HSV-tk were treated with different concentrations of GCV, TMZ, or both drugs. Cell viability was accessed by an automated microplate assay (MTT). The isobologram method and the combination index (CI) method of Chou-Talalay were used to measure the interactions between the two drugs when applied simultaneously. U87-tk and control U87 cells (5x10(6) each) were implanted in the flanks of nude mice, and animals were treated with GCV or TMZ or with both drugs. All tumors were measured and weighed at specified time points. IC(50) for GCV was 511 microM in control U87 cells and 14.3 microM in U87-tk cells, resulting in 35.7-fold increase of toxicity in the HSV-tk-expressing cells. TMZ had an IC(50) of 20.2 mM in control cells and 2.35 mM in U87-tk cells, resulting in 8.6-fold increase in sensitivity of the HSV-tk-expressing cells. TMZ and HSV-tk/GCV actions were synergistic (CI<1) in both control and U87-tk cells with higher synergism in U87-tk cells at high effect levels. Tumors expressing HSV-tk and treated with TMZ and GCV were significantly smaller than those treated by TMZ, but not by GCV. There was also a significant difference between the weight of HSV-tk expressing versus control tumors treated with TMZ, with GCV, or with both drugs. These data demonstrate synergism between HSV-tk/GCV and TMZ and higher sensitivity against TMZ in HSV-tk-expressing GBM cells. The potential importance for clinical studies combining both local tumor gene therapy and systemic chemotherapy should be explored further.
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PMID:Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma. 1159 35

Ganciclovir (GCV) is widely used as a prodrug for selective activation in tumor cells expressing herpes simplex virus thymidine kinase (HSV-TK) because of its ability to induce multi-log cytotoxicity to HSV-TK-expressing as well as nonexpressing bystander cells. We now report that another substrate for HSV-TK, D-carbocyclic 2'-deoxyguanosine (CdG), induces multi-log cytotoxicity in HSV-TK-expressing and bystander cells at concentrations <or=3 microM. We have compared the cytotoxicity and cell cycle effects of CdG to that observed with GCV in two human tumor cell lines. The results demonstrated that cytotoxicity of CdG was similar to that of GCV in both U251 glioblastoma and SW620 colon carcinoma cells that stably expressed HSV-TK. In addition, CdG induced a potent bystander effect in both cell types in co-cultures consisting of HSV-TK-expressing and nonexpressing bystander (lacZ-expressing) cells at ratios of 50:50 or 10:90. Selectivity for HSV-TK-expressing compared to lacZ-expressing cells was similar for CdG and GCV in the U251 cells, however CdG was less selective than GCV in the SW620 cell lines. Despite their ability to induce multi-log cytotoxicity at similar concentrations, CdG and GCV exhibited differential effects on cell cycle progression. Cells incubated with 1 microM CdG for 24 hr accumulated in S-phase and G(2)/M after drug washout, and the majority of cells died prior to cell division. This contrasts with the delayed effects of 1 microM GCV that were not evident until after cell division when cells attempted S-phase for the second time. Thus, CdG is a potent cytotoxic agent that merits further investigation to determine whether it will be therapeutically effective in enzyme-prodrug therapy with HSV-TK.
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PMID:Multi-log cytotoxicity of carbocyclic 2'-deoxyguanosine in HSV-TK-expressing human tumor cells. 1187 32

Controlled release of a water-soluble low-molecular-weight drug from silicone and its usefulness as a local therapeutic drug were studied. For application to ganciclovir/helpes simplex virus thymidine kinase (GCV/HSV-tk) suicide gene therapy for brain tumor, two kinds of GCV-containing silicone formulations were prepared for evaluation. In vitro, GCV release from matrix-type formulation consisting of a single matrix was characterized by Fickian diffusion, while covered-rod-type formulation, in which the side surface of the outer layer was covered with 100% silicone, exhibited a near-zero-order release pattern. In an in vivo study using a rat 9L glioblastoma model, administration of GCV-silicone formulation into brain tumor yielded sustained intracerebral GCV concentration for 4 days after administration, with excellent antitumor effect equal to or better than that of daily intraperitoneal administration of aqueous solution of GCV, at a dose less than 1/100 of the total dose of solution for intraperitoneal administration. Furthermore, GCV was undetectable in blood, suggesting that decrease in systemic adverse reactions can be expected with intracerebral administration of GCV-silicone formulation.
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PMID:New drug delivery system for water-soluble drugs using silicone and its usefulness for local treatment: application of GCV-silicone to GCV/HSV-tk gene therapy for brain tumor. 1239 64

The ability of herpes simplex virus type 1 thymidine kinase (HSV-tk)-expressing cells incubated with ganciclovir (GCV) to induce cytotoxicity in neighboring HSV-tk-negative (bystander) cells has been well documented. Although it has been suggested that this bystander cell killing occurs via the transfer of phosphorylated GCV, the mechanism(s) of this bystander effect and the importance of gap junctions for the effect of prodrug/suicide gene therapy in primary human glioblastoma cells remains elusive. Surgical biopsies of malignant gliomas were used to establish explant primary cultures. Proliferating tumor cells were characterized immunohistochemically and found to express glial tumor markers including nestin, vimentin, glial fibrillary acidic protein (GFAP), S-100, and gap junction protein connexin 43 (Cx43). Western blot analysis revealed the presence of phosphorylated isoforms of Cx43 and Calcein/DiI fluorescent dye transfer showed evidence of efficient gap junction communication (GJC). In order to study the effect(s) of prodrug/suicide gene therapy in these cultures, human glioblastoma cell cultures were transfected with the HSVtk gene for transient or stable expression. Ganciclovir treatment of these cultures led to >90% of cells dead within 1 week. Eradication of cells could be inhibited by the addition of alpha-glycyrrhetinic acid (AGA), a GJC inhibitor. In parallel experiments, AGA decreased the immunodetection of phosphorylated Cx43 as analyzed by Western blot and inhibited fluorescent dye transfer. In conclusion, these observations are consistent with GJC as the mediator of the bystander effect in primary cultures of human glioblastoma cells by the transfer of phosphorylated GCV from HSVtk gene transfected cells to untransfected ones.
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PMID:Gap junction-mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSVtk gene. 1265 Nov 52

Our laboratory has employed replication-defective herpes simplex virus type 1 gene transfer vectors for treatment of animal models of human malignant glioblastoma. The base vectors were defective for the immediate early (IE) genes ICP4, ICP27, and ICP22 but expressed the IE gene ICP0, which can arrest tumor cell division, and an IE thymidine kinase (alpha-tk) gene construct that mediates suicide gene therapy (SGT) in the presence of ganciclovir (GCV). Previously, we reported that SGT using ICP0/alpha-tk vectors in nude mouse models of glioblastoma was improved by coexpression of the gap-junction-forming protein connexin43 (Cx43) or human tumor necrosis factor alpha (TNF alpha). We also showed that further gains in therapeutic outcome could be achieved by combining TNF alpha-enhanced SGT with gamma-knife radiosurgery (GKR). To expand these observations, we have first repeated these studies in immunocompetent rats with brain tumors derived from implanted 9L gliosarcoma cells and second compared the most efficient vector from this study with a new recombinant vector, NUREL-C2, which expressed both TNF alpha and Cx43 along with ICP0 and alpha-tk. Results from the first part indicated that our ICP0/alpha-tk/TNF alpha vector in combination with GKR provides an effective therapy although this treatment was not statistically better than GKR combined with the ICP0/alpha-tk/Cx43 vector. Our observations in the second part suggested that NUREL-C2 may be more effective than the ICP0/alpha-tk/TNF alpha vector in combination treatments with GCV (P = 0.08) or GCV plus GKR (P = 0.10). GKR significantly enhanced the efficacy of NUREL-C2/GCV treatment (P = 0.02) as well as other virus/GCV treatments (P < or = 0.05). Conversely, the efficacy of GKR was significantly improved by both the ICP0/alpha-tk/TNF alpha vector and NUREL-C2 in combination with GCV (P = 0.02 and P < 0.01, respectively). Together these results indicate that NUREL-C2 may be an attractive candidate for Phase I gene-therapy safety studies in patients with recurrent malignant glioblastoma.
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PMID:Treatment of rat gliosarcoma brain tumors by HSV-based multigene therapy combined with radiosurgery. 1452 25

The management of patients with glioblastoma remains challenging with an average survival of 32-56 weeks. We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC). Entry criteria for this study included: recurrent malignant glioma after surgical resection and conventional radiation therapy. At the time of recurrence, computerized volumetric resection of the tumor was performed and the ADV/HSV-tk complex was injected in the tumor bed. GC was administered 24 h after surgery (10 mg/kg/day) for 7 days. Patients were divided into 3 ADV/HSV-tk dose-escalating cohorts. Adenoviral vector shedding, and local or systemic toxicity did not occur in this study. Magnetic resonance imaging showed lack of increased brain edema in the treated patients. Histological examination of the 5 patients that had repeated surgery after gene therapy treatment showed lack of tissue toxicity. Additionally, PCR for HSV-tk was negative in the brain 3 months after injection. The patients' Karnofsky score was maintained > or = 70 in 8/10 patients (80%) and 5/9 patients (55%) 3 and 6 months respectively, after gene therapy. Ten of 11 patients survived > or = 52 weeks from diagnosis with an average survival of 112.3 weeks. One patient is still alive 248 weeks from diagnosis. These data show that the ADV/HSV-tk/GC complex at the dose used in this study is safe. Additional dose escalation is currently in progress.
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PMID:Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. 1468 78

Historically, in vivo imaging methods have largely relied on imaging gross anatomy. More recently it has become possible to depict biological processes at the cellular and molecular level. These new research methods use magnetic resonance imaging (MRI), positron emission tomography (PET), near-infrared optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of primary interest is the development of methods using MRI and PET with which the progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase) and Parkinson's disease can be monitored and graphically displayed. The distribution of serotonin receptors in the human brain and the duration of serotonin-receptor antagonist binding can be assessed by PET. With PET, it is possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR tracking of transplanted oligodendrocyte progenitors is feasible for determining the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult rats with subventricular zone cells can be monitored by MRI. Transgene expression (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be visualized using MRI. Macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases and cathepsin B can improve the assessment of tumor aggressiveness and angiogenesis-inhibitory therapy. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity and annexin B. This review demonstrates the need for neurohistological research if further progress is to be made in the emerging but burgeoning field of molecular imaging.
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PMID:Molecular imaging: Bridging the gap between neuroradiology and neurohistology. 1502 22

Tumor targeting is an important issue in cancer gene therapy. We have developed a gene transfection method, based on light-inducible photochemical internalization (PCI) of a transgene, to improve gene delivery and expression selectively in illuminated areas, for example, in tumors. In the present work, we demonstrate that PCI improved the nonviral vector polyethylenimine (PEI)-mediated transfection of a therapeutic gene, the 'suicide' gene encoding herpes simplex virus thymidine kinase (HSVtk). In U87MG glioblastoma cells in vitro, the photochemical treatment stimulated expression of the HSVtk transgene, and, consequently, enhanced cell killing by the subsequent treatment with the prodrug ganciclovir (GCV). When relatively low doses of DNA (1 microg/ml) and the PEI vector (N/P 4) were used, HSVtk gene transfection followed by the GCV treatment did not have an effect on cell survival unless the photochemical treatment was performed, which potentiated the cytotoxicity to 90%. These findings indicate that photochemical transfection allows: (i) selective enhancement in gene expression and gene-mediated biological effects (cell killing by the Hsvtk/GCV approach) in response to illumination; (ii) the use of low, suboptimal for the nonviral transfection methods without PCI, doses of both DNA and the vector, which may be relevant and advantageous for therapeutic gene transfer in vivo.
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PMID:Photochemically enhanced gene transfection increases the cytotoxicity of the herpes simplex virus thymidine kinase gene combined with ganciclovir. 1511 58

Gene therapy of glioma based on viral delivery of herpes simplex virus type I thymidine kinase (HSV-TK) has failed in the clinic because of low transduction efficacy. To circumvent this problem, this study evaluated highly migratory HSV-TK-transduced neural stem cells (NSC) for their ability to kill untransduced glioma cells by a gap junction-mediated bystander effect. The admixture of HSV-TK-transduced NSC to U87MG and LN-18 human malignant glioma cell lines at ratios of 1:10 or 1:1 eliminated more than 50% or 90% of glioma cells in the presence of ganciclovir (25 microM). Glioma cell cytotoxicity required cell-cell contact. Similarly, tumor cell cytotoxicity was observed in two of three primary glioblastoma cell cultures, and the presence of this bystander effect correlated with the expression of connexin 43 in the untransduced glioma target cells. In conclusion, we delineate a role for migratory HSV-transfected NSC to eliminate glioma cells purely by means of the bystander effect.
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PMID:Migratory neural stem cells for improved thymidine kinase-based gene therapy of malignant gliomas. 1567 Jul 59

To improve the effectiveness of herpes simplex virus (HSV) thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy, the replication-defective HSV vector TOIkappaB expressing both HSV-TK and a mutant form of the NF-kappaB inhibitor IkappaBalpha (IkappaBalphaM) was developed. TOIkappaB was constructed by recombining the IkappaBalphaM gene into the U(L)41 locus of a replication-defective lacZ expression vector, TOZ.1. Expression of IkappaBalphaM was confirmed by Western blotting, and the ability of the mutant protein to inhibit NF-kappaB nuclear translocation was examined by electrophoretic mobility shift assay. In human glioblastoma U-87MG cells, the p50/p50 dimer of NF-kappaB was already translocated to the nucleus without receptor-dependent signaling by TNF-alpha. Following infection with TOIkappaB, nuclear translocation of NF-kappaB in U-87MG cells was significantly inhibited and caspase-3 activity increased compared with TOZ.1-infected cells. The cytotoxicity of TOIkappaB for U-87MG cells was investigated by colorimetric MTT assay. At an MOI of 3, TOIkappaB infection killed 85% of the cells compared to 20% killed by TOZ.1 infection. In the presence of GCV, these numbers increased to 95-100% for TOIkappaB and 80-85% for TOZ.1. TOIkappaB neurotoxicity measured on cultured murine neurons was relatively low and similar to that of TOZ.1. The survival of nude mice implanted into the brain with U-87MG tumor cells was markedly prolonged by intratumoral TOIkappaB injection and GCV administration. Survival of TOIkappaB+GCV group was significantly longer (P<.02, Wilcoxon test) than for the control groups (TOZ.1 or TOIkappaB only, PBS or PBS+GCV). These results suggest that IkappaBalphaM expression may be a safe enhancement of replication-defective HSV-based suicide gene therapy in vitro and in vivo.
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PMID:Combination gene therapy for glioblastoma involving herpes simplex virus vector-mediated codelivery of mutant IkappaBalpha and HSV thymidine kinase. 1569 8

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