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

Thymidine kinase negative (dTK-) mutants of herpes simplex virus type 1 (HSV-1) multiplied well in rat brain glioma cells. A proportion (less than 1%) of glioma cells survived the infection with HSV and were designated "survivor" glioma cells. Survivor cells of dTK- mutant virus infection ceased to produce infectious virus after two passages and were highly resistant to both HSV-1 and HSV-2 but not to vesicular stomatitis virus (VSV). Flow cytometric studies indicated morphological differences between parental and survivor glioma cells, and HSV-1 specific antigens as well as DNA were detected in the survivor glioma cells, but only in early passages. Sensitivity to superinfection with HSV appears to correlate to loss of HSV-specific viral DNA in the survivor glioma cells. Survivor glioma cells after several subcultures lost their ability to resist superinfecting HSV, reverted morphologically to the appearance of parental glioma cells and also lost significant amount of HSV-1 specific DNA. These transient survivor glioma cells became persistently infected-virus producer cells upon HSV infection.
 ...
PMID:Studies on interactions of dTK-HSV mutants with neurons in vitro. 287 27

Rat brain glioma cells were semipermissive for herpes simplex virus (HSV) replication, because the growth of HSV was multiplicity-dependent in these cells. By using this property, we successfully isolated 'survivor' glioma cells following HSV infection at low multiplicity and without using any special treatment (such as UV irradiation) either of the cells or of the virus. Under the same conditions there were no survivor BHK or 3T3 cells, which suggests the uniqueness of the glioma cell-HSV interaction. The survivor cells ceased to produce infectious virus after two subcultures, but were highly resistant to superinfection for at least 20 subcultures. Parental cells were significantly more permissive for homologous virus growth than survivor cells. Interferon was apparently not induced in the survivor cells, because they were as susceptible as the parental cells to infection with vesicular stomatitis virus. The survivor cells produced HSV-specific antigens and contained HSV-specific DNA.
 ...
PMID:Herpes simplex virus type 1 and neuronal cells--a special cell-virus interaction. 298 13

Herpes simplex virus (HSV) is a large DNA virus with unique properties that can be exploited for in vivo gene therapy. HSV is neurotropic, establishes latency, and has a large transgene capacity. These properties can be utilized in therapy of nervous system diseases. Wild-type HSV and the vectors derived from it induce both innate and acquired immune response. However, HSV is skillful in escaping the host response. It has evoked mechanisms including avoidance of antigen presentation on major histocompatibility (MHC) molecules, inhibition of host interferon response, impairment of the antibody and complement responses, and inhibition of apoptosis in infected cells. One of the molecules affecting the interferon response is ICP34.5, encoded by the so-called neurovirulence gene gamma(1)34.5. The mutants deleted of this gene are non-neurovirulent, having ca 3000-fold decreased ability to replicate in CNS. The HSV vectors based on the gamma(1)34.5 deletion mutants show efficacy against glioma and in other cancer therapies. These mutants provide an interesting platform for developing safe and efficient gene delivery for numerous neurological diseases or brain tumors. The immune response evoked by the HSV vector is central in determining the spread and persistence of the vector, and its transgene expression, and in controlling the innate and adaptive immune response against effective spread of the vector. These questions are key issues of herpesviral gene therapy and cancer therapy at the moment. This review describes the involvement of immune response in HSV infection and in gamma(1)34.5 deletion HSV-based virotherapy. We discuss the challenge of developing vectors with desired immune response benefiting the therapy and maintaining the efficiency.
 ...
PMID:Immune response to herpes simplex virus and gamma134.5 deleted HSV vectors. 1625 Aug 92

Oncolytic herpes simplex virus (HSV) vectors have been used in early phase human clinical trials as a therapy for recurrent malignant glioblastoma. This treatment proved safe but limited improvements in patient survival were observed. The potency of these vectors might be enhanced by targeting vector infectivity to tumor cells. Glioma tumors often express a mutant form (vIII) of the epidermal growth factor receptor (EGFR) resulting in the presence of a novel epitope on the cell surface. This epitope is specifically recognized by a single-chain antibody designated MR1-1. HSV-1 infection involves initial binding to heparan sulfate (HS) on the cell surface mediated primarily by the viral envelope, glycoprotein C (gC). Here we joined the MR1-1 single-chain antibody (scFv) to the gC sequence deleted for the HS-binding domain as a means of targeting viral attachment to EGFRvIII on glial tumor cells. Virions bearing MR1-1-modified gC had fivefold increased infectivity for EGFRvIII-bearing human glioma U87 cells compared to mutant receptor-deficient cells. Further, MR1-1/EGFRvIII-mediated infection was more efficient for EGFRvIII-positive cells than was wild-type virus for either positive or negative cells. Sustained infection of EGFRvIII+ glioma cells by MR1-1-modified gC-bearing oncolytic virus, as compared to wild-type gC oncolytic virus, was also shown in subcutaneous tumors in vivo using firefly luciferase as a reporter of infection. These data show that HSV tropism can be manipulated so that virions recognize a cell-specific binding site with increased infectivity for the target cell. The retargeting of HSV infection to tumor cells should enhance vector specificity, tumor cell killing and vector safety.
 ...
PMID:Targeting HSV-1 virions for specific binding to epidermal growth factor receptor-vIII-bearing tumor cells. 2050 70

Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient virus replication in tumor cells. This disappointing outcome can be attributed in part to attenuating mutations engineered into these viruses to prevent replication in normal cells. Alternatively, retargeting of fully replication-competent HSV to tumor-associated receptors has the potential to achieve tumor specificity without impairment of oncolytic activity. Here, we report the establishment of an HSV retargeting system that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. We demonstrate efficacy in vitro and in a heterotopic tumor model in mice. Evidence for systemically administered virus homing to the tumor mass is presented. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. Our study describes an approach to HSV retargeting that is effective in a glioma model and may be applicable to the treatment of a broad range of tumor types.
 ...
PMID:Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. 2307 Jan 15