Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene transfer with vectors derived from murine retroviruses is restricted to cells which are proliferating and synthesizing DNA at the time of infection. This suggests that retroviral-mediated gene transfer might permit targeting of gene integration into malignant cells in organs composed mainly of quiescent nonproliferating cells, such as in the brain. Accordingly, selective introduction of genes encoding for susceptibility to otherwise nontoxic drugs ("suicide" genes) into proliferating brain tumors may be used to treat this cancer. We investigated the efficacy and dynamics of in vivo transduction of growing brain tumors with the herpes simplex-thymidine kinase gene followed by administration of the antiviral drug ganciclovir. Ganciclovir is phosphorylated by thymidine kinase to toxic triphosphates that interfere with DNA synthesis, resulting in the preferential death of the transduced tumor cells. Rats inoculated with 4 x 10(4) 9L gliosarcoma cells into the frontal lobe were treated 7 days later with an intratumoral stereotaxic injection of murine fibroblasts (NIH 3T3 cells) that were producing a retroviral vector containing the herpes simplex-thymidine kinase gene. Controls received vector producer and nonproducer NIH 3T3 cell lines containing the Escherichia coli lacZ (beta-galactosidase) gene as well as nonproducer NIH 3T3 cells containing the thymidine kinase gene. The animals were rested for 7 days to allow time for in situ transduction of the proliferating tumor cells with the herpes-thymidine kinase retroviral vector. The animals were then treated with ganciclovir, 15 mg/kg i.p. twice a day for 14 days. Gliomas receiving an injection of 3-5 x 10(6) thymidine kinase producer cells regressed completely in 23 of 30 rats given ganciclovir therapy, while 25 of 26 control rats developed large tumors. Intratumoral injection of a lower concentration of thymidine kinase vector producer cells (1.8 x 10(6)) resulted in a lower frequency of tumor regression (5 of 13 rats). To estimate the efficiency of in vivo gene transfer, 9L brain tumors were given injections of 5 x 10(6) beta-galactosidase vector producer cells. 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranaside staining revealed maximal staining of beta-galactosidase within the tumor 7-14 days after injection of the vector producer cells. In vivo transduction rates in harvested tumors ranged from 10 to 70%. There was no evidence of transduction of the surrounding normal neural tissue. Occasional blood vessel endothelial cells within or adjacent to the tumor were observed to be 5-bromo-4- chloro-3-indolyl-beta-D-galactopyranaside positive.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. 803 19

Malignant gliomas are the most common malignant brain tumors and are almost universally fatal. A genetically engineered herpes simplex virus-1 mutant with decreased neurovirulence, dlsptk, has been shown to kill human glioma cells in culture and in animal models. However, intracranial inoculation of dlsptk is limited by fatal encephalitis at higher doses. Therefore, additional engineered and recombinant herpes simplex mutants with demonstrated reduced neurovirulence (AraAr9, AraAr13, RE6, R3616) were examined as antiglioma agents. One long-term human glioma cell line and two early-passage human gliomas in culture were destroyed by all four viruses tested. In a subcutaneous glioma model, AraAr13, RE6, and R3616 retained substantial antineoplastic effects in nude mice when compared with controls (one-sided Wilcoxon rank test, P < 0.05 for one or more doses each). When tested in a nude mouse intracranial glioma model, both RE6 and R3616 significantly prolonged average survival without producing premature encephalitic deaths at two doses (log-rank statistic, P < 0.007). Histopathological studies of the brains of surviving animals revealed minimal focal encephalitis in two of three RE6-treated animals and no evidence of encephalitis in either one of three RE6-treated or in three of three R3616-treated animals. No evidence of residual tumor was seen in four of the six surviving animals. Additionally, both RE6 and R3616 were found to be susceptible to the common antiherpetic agent acyclovir, adding to their safety as potential antiglioma agents. Recombinant and engineered viruses that minimize host toxicity and maximize tumoricidal activity merit further study as antineoplastic agents.
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PMID:Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir. 838 43

Imaging the expression of successful gene transduction has been demonstrated in vivo for the first time by using an appropriate combination of "marker gene" and "marker substrate" in an experimental animal model. The herpes simplex virus 1 thymidine kinase (HSV1-tk) gene was selected as an example of a marker gene, and the recombinant STK retrovirus containing HSV1-tk was used to transduce RG2 glioma cells in vitro and in vivo. RG2TK+ cell lines expressing the HSV1-tk gene and three potential marker substrates for the HSV1-TK enzyme were evaluated. Radiolabeled 5-iodo-2'-fluoro-2'deoxy-1-beta-D-arabinofuranosyluracil (FIAU) was shown to be a substantially better marker substrate for the HSV1-TK enzyme than 5-iodo-2'-deoxyuridine or ganciclovir. The magnitude of FIAU accumulation in different RG2TK+ clones corresponded to their sensitivity to ganciclovir and to the level of HSV1-tk mRNA expression. Imaging the expression of HSV1-tk in transduced RG2 tumor cells was demonstrated in animals using quantitative autoradiography; 2-[14C]FIAU accumulation was shown to be high in RG2TK+ brain tumors growing in one hemisphere and very low in nontransduced RG2 tumors in the contralateral hemisphere. Transduction of RG2 tumor cells with the HSV-tk gene in vivo resulted in tumors which accumulated FIAU to high levels and produced clearly defined images. Given the level of FIAU accumulation in the transduced tumors, it is likely that a clinically applicable method for imaging HSV1-tk gene expression can be implemented using existing clinical imaging techniques.
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PMID:Imaging the expression of transfected genes in vivo. 852 3

Transfer of the herpes simplex virus type-1 thymidine kinase (HSV-tk) gene into tumor cells followed by ganciclovir (GCV) administration, will provide selective tumor cell killing. We studied the effect of herpes simplex virus thymidine kinase (HSV-tk) expression level on the HSV-tk/GCV-mediated "bystander effect." Clones of HSV-tk-transduced rat glioma cells (9L) were isolated that stably expressed with different levels of HSV-tk. All clones studied had similar sensitivity to ganciclovir with IC50 values ranging from 0.45 to 1.3 microM. Within certain enzyme level thresholds, in vitro evaluation of the bystander effect has shown that clones with higher level of HSV-tk expression exhibited a better bystander effect. Interestingly, the bystander effect was observed between different cell types. Both the transduction efficiency and bystander effect are essential factors for the success of the antitumor effect by the HSV-tk/prodrug GCV suicide gene system.
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PMID:Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir-mediated cytotoxicity and the "bystander effect". 857 19

Herein we describe experiments showing that the early growth response gene 1 (EGR-1) promoter is sufficient to confer selective expression of the luciferase gene (Luc) in glioma cell lines exposed to ionizing radiation. Activity of the EGR-1 promoter was investigated in human glioblastoma cells using the plasmid vector, pEGR-Luc. The EGR-1 promoter gene directed radiosensitive expression of luciferase. This promoter showed high levels of activity (10-fold) in irradiated glioma cell lines as compared to basal levels of activity in nonirradiated cell lines. Maximum activation was detectable at 1-3 hr after stimulation with 20 Gy. The results also demonstrate that cells modified to contain the herpes simplex virus-thymidine kinase (HSV-tk) gene under control of the EGR-1 promoter become sensitive to treatment with the antiviral agent ganciclovir (GCV), whereas nonirradiated cells and nontransfected cells were unaffected by this agent. This results suggest that therapeutic genes can be expressed selectively in irradiated glioma cells. The results also indicate that the EGR-1 promoter can be used to induce exogenous genes selectively in radiation fields used for the treatment of malignant brain tumors.
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PMID:Activation of the radiosensitive EGR-1 promoter induces expression of the herpes simplex virus thymidine kinase gene and sensitivity of human glioma cells to ganciclovir. 866 75

The herpes simplex virus thymidine kinase gene was transferred into C6 glioma cells by infection with a recombinant adenovirus. In vitro, a 10 microM ganciclovir concentration was able to kill 100% of the infected cells. For in vivo experiments, brain tumors were established by stereotactic injection of C6 glioma cells in the caudate nucleus of rats. Five days later, the recombinant adenovirus was inoculated into the tumors and the animals were treated by intraperitoneal injections of ganciclovir for 14 days. At the end of ganciclovir therapy, histological examination revealed a 28-fold decrease in tumor volumes in the treated animals, as compared with control animals. In long-term studies, the mean survival time of the treated animals were four-fold longer than that of control ones. Magnetic resonance imaging demonstrated an apparent complete tumor regression in 62% of the animals. However, late tumor recurrence was observed in the treated animals. Repeated inoculation of C6 glioma cells in the contralateral hemisphere of long-term surviving animals resulted in either tumor rejection or slowly growing tumors. These findings demonstrate the potential efficacy of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration in the treatment of rat gliomas.
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PMID:Gene therapy of rat C6 glioma using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene: long-term follow-up by magnetic resonance imaging. 873 63

Primary tumours of the central nervous system (CNS) are an important cause of cancer-related deaths in adults and children. CNS tumours are mostly glial cell in origin and are predominantly astrocytomas. Conventional therapy of high-grade gliomas includes maximal resection followed by radiation treatment. The addition of adjuvant chemotherapy provides little improvement in survival time and hence assessment of novel therapies is imperative. We have evaluated the potential therapeutic use of the herpes simplex virus (HSV) mutant 1716 in the treatment of primary brain tumours. The mutant is deleted in the RL1 gene and fails to produce the virulence factor ICP34.5. 1716 replication was analysed in both established human glioma cell lines and in primary cell cultures derived from human tumour biopsy material. In the majority of cultures, virus replication occurred and consequential cell death resulted. In the minority of tumour cell lines which are non-permissive for mutant replication, premature shut-off of host cell protein synthesis was induced in response to lack of expression of ICP34.5. Hence RL1-negative mutants have the distinct advantage of providing a double hit phenomenon whereby cell death could occur by either pathway. Moreover, 1716, by virtue of its ability to replicate selectively within a tumour cell, has the potential to deliver a 'suicide' gene product to the required site immediately. It is our opinion that HSV which fails to express ICP34.5 could provide an effective tumour therapy.
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PMID:Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours--evaluation of a potentially effective clinical therapy. 879 77

Noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression is possible with a clinical gamma camera and by single-photon emission tomography (SPECT) using 131I-labeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodo-uracil (FIAU). Studies were performed in rats bearing s.c. tumors. Tumors were produced by injection of wild-type RG2 glioma or W256 mammary carcinoma cells into one flank and RG2TK+ glioma or W256TK+ mammary carcinoma cells (that had been transduced in vitro with the HSV1-tk gene) into the opposite flank. In some animals, HSV1-tk gene transduction of the pre-established wild-type tumors was accomplished in vivo by direct intratumoral injection of retroviral vector-producer cells. Imaging studies were performed 2 weeks after tumor transduction to allow time for production and spread of the retroviruses through the tumor and for sufficient growth and increase in size of the tumors to facilitate imaging. The gamma camera and SPECT images revealed highly specific localization of [131I]FIAU-derived radioactivity to areas of HSV1-tk gene expression at 24, 36, and 48 h after i.v. administration of 1.6-2.8 mCi of [131I]FIAU. Comparative analysis of quantitative autoradiographic images obtained from the same tumors confirmed that the high levels of [131I]FIAU-derived radioactivity (> 1% dose) were localized to areas of HSV1-tk gene expression demonstrated by immunohistochemical staining for HSV1-tk protein. In contrast, significantly lower levels of [131I]FIAU-derived radioactivity (< 0.01%) were observed in the surrounding nontransduced tumor tissue, contralateral wild-type tumors, and other tissues that showed no immunohistochemical staining for the HSV1-tk protein. The magnitude of FIAU accumulation in RG2TK+, W256TK+, and wild-type tumors corresponded to the in vitro ganciclovir sensitivity of the cell lines used to produce these tumors, which indicates that the magnitude of FIAU accumulation reflects the level of HSV1-tk gene expression. We suggest that "clinically relevant" levels of HSV1-tk gene expression in transfected tissue can be imaged with [131I]FIAU and a gamma camera or SPECT, and that a significant improvement in imaging sensitivity and resolution is expected with [124I]FIAU and PET.
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PMID:Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy. 879 71

Due to lack of effective therapy, primary brain tumors are the focus of intense investigation of novel experimental approaches that use vectors and recombinant viruses. Therapeutic approaches have been both indirect, whereby vectors are used, or direct to allow for direct cell killing by the introduced virus. Genetically engineered herpes simplex viruses are currently being evaluated as an experimental approach to eradicate malignant human gliomas. Initial studies with gamma (1)34.5 mutants, R3616 (from which both copies of the gamma (1)34.5 gene have been deleted) and R4009 (a construct with two stop codons inserted into the gamma (1)34.5 gene), have been assessed. In a syngeneic scid mouse intracranial tumor model, recombinant herpes simplex virus can be experimentally used for the treatment of brain tumors. These viruses and additional engineered viruses were subsequently tested in human glioma cells both in vitro and in vivo. Using a xenogeneic scid mouse intracranial glioma model, R4009 therapy of established tumors significantly prolonged survival. Most importantly, long-term survival was achieved, with histologic evidence that R4009 eradicated intracranial tumors in this model. Furthermore, the opportunity to evaluate gamma (1)34.5 mutants that have enhanced oncolytic activity, e.g., R8309 where the carboxyl terminus of the gamma (1)34.5 gene has been replaced by the murine homologue, MyD116, are considered.
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PMID:The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors. 887 32

The efficacy of gene therapy for glioma was examined using adeno-associated virus (AAV)-based vectors to deliver genes to experimental tumors in mice. Stereotactic injection of 2 x 10(5) U-251SP human glioma cells into the brains of nude mice produced tumors of 19.06 +/- 1.79 mm2 17 days after injection. Employing a high titer preparation of AAV vector containing the gene for beta-galactosidase (AAV-lacZ), dose-dependent transduction of U-251SP cells was seen in vitro. When 1.6 x 10(10) AAV-lacZ particles were directly injected into tumors in vivo, 30-40% of the cells along the needle track expressed beta-galactosidase. Transduction of U-251SP cells in vitro with an AAV vector containing a bicistronic gene encoding both herpes simplex thymidine kinase and human interleukin-2 (AAV-tk-IRES-IL2) rendered them sensitive to the cytocidal effects of ganciclovir (GCV) and IL-2 was produced in a dose-dependent manner. Cocultures of AAV-tk-IRES-IL2 transduced cells and nontransduced cells proved highly sensitive to GCV indicating the contribution of the bystander effect. Stereotactic delivery of 6 x 10(10) AAV-tk-IRES-IL2 particles into day 7 tumors in nude mice followed by administration of GCV for 6 days, resulted in a 35-fold reduction in the mean volume of tumors compared with controls. Normal brains did not suffer from any toxic effect of the administration of AAV-tk-IRES-IL2 and GCV. These results indicate that high titer AAV vector treatment may be safe and effective for in vivo gene therapy of human brain tumors.
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PMID:Gene therapy against an experimental glioma using adeno-associated virus vectors. 894 Jun 35


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