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 ( 5Â10 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 M in control U87 cells and 14.3 M 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 -tkexpressing 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. Cancer Gene Therapy ( 2001 ) 8, 662 -668
Increased expression of gamma-glutamyltransferase (GGT) has been detected in a range of human malignancies and is thought to be involved in neoplastic proliferation and treatment resistance. Since GGT expression and its role in malignant glioma biology remain largely unknown, we investigated this phenomenon by immunostaining 26 higher-grade human astrocytic gliomas (WHO grades III and IV) with a monoclonal anti-GGT-antibody (138H11). Further, human pancreatic GGT cDNA was used for liposome-mediated transfection of 9L gliosarcoma cells. GGT-expressing and control 9L cells were cultured in media containing different amounts of essential amino acids and/or cytotoxic agents. Cell viability was evaluated by microplate MTT assay. Immunohistochemical staining of tumor specimens demonstrated that GGT expression is a frequent feature of higher-grade human astrocytic gliomas, but not of normal brain tissue. Human tumors were strongly GGT-positive in 6 of 7 cases of grade III astrocytoma, and in 12 of 19 grade IV astrocytoma (glioblastoma multiforme, GBM) cases. In the cell culture model, 9L-GGT cells had a growth advantage over control cells in cysteine-deficient medium. but not in standard or glutamine-free medium. No significant difference in numbers of viable cells of either clone was found in media containing the alkylating drug BCNU (5-200 microg/ml). In conclusion, GGT is expressed in a high percentage of human WHO grade III astrocytomas and GBM, but not in normal brain tissue. This molecule seems to give neoplastic cells a moderate growth advantage under in vivo conditions.
Hemophagocytic lymphohistiocytosis is a rare and fatal disorder of early infancy, which affects predominantly the mononuclear phagocyte system and is characterized by the presence of fever, hepatosplenomegaly and cytopenia. Neurological symptoms can be extremely variable, ranging from irritability, and convulsions to focal neurological signs. They often develop during disease progression, but can also be the leading initial symptoms. Early diagnosis is mandatory, because new treatments, including bone marrow transplantation, appear to be promising. Here we present the clinical, neuroradiological and histopathological findings from two children with progressive CNS disease as the main clinical manifestation of hemophagocytic lymphohistiocytosis. Both children died and diagnosis was only obtained in retrospect after careful review of the histopathological material.
Bcl-2 protein plays an important role in inhibiting apoptosis and protecting normal and neoplastic cells from toxicity. Bcl-2 overexpression in malignant tumors, on the other hand, may cause resistance against adjuvant treatment. Since there are subpopulations of patients with glioma that differ considerably in their treatment benefit, it is important to identify prognostic factors for outcome and to tailor adjuvant protocols in accordance with specific biological features of the respective tumor. The present study aimed at investigating the role of bcl-2 expression in higher-grade glioma (WHO grade III and IV). Bcl-2 expression was correlated with clinical and paraclinical parameters, and evaluated in univariate and multivariate statistical models. In addition, bcl-2-overexpressing human glioma cells in culture were used for modeling the in vivo findings and for investigating the importance of bcl-2 for tumor resistance against cytotoxic treatment. A group of 86 patients with higher-grade glioma were investigated. Anaplastic astrocytoma (AA; WHO G III, n = 29) showed bcl-2 expression in 48% of the cases, and immunohistochemical positivity was associated with a significantly shorter survival time (p = 0.0068). In glioblastoma patients (GBM; WHO G IV, n = 57), 51% of tumors were bcl-2 positive, but bcl-2 expression did not correlate significantly with survival (p = 0.39). In a Cox proportional hazards regression model, bcl-2 positivity was confirmed as a negative prognostic parameter in AA, but not in GBM. Bcl-2 overexpressing and control human glioma cell clones (T98MG line) were treated in culture with the cytotoxic drugs carmustine (BCNU), paclitaxel, vincristine, and doxorubicin. In addition, bcl-2-overexpressing and control cells were infected with a retrovirus carrying the herpes-simplex-virus thymidine kinase gene (HSV-tk), and then treated with ganciclovir (GCV). Bcl-2 overexpression significantly increased tumor cell resistance against all of the above cytotoxic drugs, and also against HSV-TK/GCV mediated gene therapy.
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