Neurosurg Focus
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Despite recent advances in operative techniques, chemotherapy, and radiotherapy, the prognosis in patients with glioblastoma multiforme (GBM) remains poor; the majority die within a year of diagnosis. Although often effective at reducing mass effect and tumor burden, surgical debulking and cytotoxic therapies have never demonstrated an unequivocally significant benefit in treating patients with GBM. This shortcoming has led to the development of molecules that target specific steps in the transduction pathways of high-grade glioma cells. In this article the authors review various cellular and extracellular signaling pathways that may prove promising in the treatment of patients with malignant glioma.
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Established treatments such as surgery, radiation, and chemotherapy have only minimally altered the median survival time of patients with glioblastoma multiforme, the most common malignant brain tumor. These failures reflect the highly invasive nature of the disease, as well as the fact that few cells are actively dividing at any given time. ⋯ Over the past decade, laboratory studies and early clinical trials have raised the hope that these therapeutic requirements may be fulfilled by gene therapy in which nonreplicating transgene-bearing viruses, oncolytic viruses, or migratory stem cells are used to deliver tumoricidal transgenes. The authors review the principles behind these approaches and their initial results.
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Adenovirus transduction in gene therapy is dependent on the expression of the coxsackie virus-adenovirus receptor (CAR) for initial binding and on the integrin receptors (avb3, avb5) for viral internalization. Low and variable expression of CAR may be responsible for the low transduction rates seen with native adenoviral vectors. The goal of this study was to demonstrate increased transduction efficiency by retargeting the adenovirus with a fibroblast growth factor (FGF) ligand, FGF-2. ⋯ Fibroblast growth factor-2-retargeted adenoviral vectors may be used to increase the transduction of GBM-derived endothelial cells, enabling a new and efficient antiangiogenesis strategy for the treatment of malignant gliomas.
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Because the prognosis for patients with glioblastoma multiforme (GBM) remains poor, investigators have focused on developing new and more effective treatment modalities. Targeted toxins represent a new class of compounds composed of a potent protein toxin and a carrier ligand that will recognize cell surface antigens located on target tissue. A recombinant fusion protein was created that contains the translocation and catalytic portions of diphtheria toxin that are responsible for cell entry and killing, respectively, fused to the noninternalizing aminoterminal fragment portion of human plasminogen activator. This diptheria toxin-uPA fusion protein (DTAT) has the advantage over other fusion proteins of targeting malignant glioma cells and the endothelial cells of the neovasculature that express the urokinase-type plasminogen activator receptor (uPAR). Another protein, DTAT13, was synthesized to target uPAR on the neovasculature and the uPAR and interleukin-13 receptor-expressing GBM cells. The authors describe the in vitro and in vivo efficacy of DTAT and DTAT13 against GBM. ⋯ Both DTAT and DTAT13 might have potential for clinical application against GBM because of their ability to target both the tumor cells and neovasculature simultaneously with an absence of serious systemic side effects. The discovery that DTAT13 was less toxic than DTAT indicated that the bispecific fusion protein might target a broader subset of antigenetically diverse patients with tumors while reducing the systemic exposure to toxin that would be necessary if two agents were administered separately.