Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy

Abstract

BACKGROUND Malignant gliomas of the central nervous system remain associated with dismal prognoses because of their diffuse invasion of the brain parenchyma. Very few experimental models that mimic clinical reality are available today to test potentially new therapies. The authors set up experimental in vivo glioma models of anaplastic astrocytomas of human and rat origins and anaplastic oligodendroglioma of human origin. Standard hospital chemotherapies were employed to test the validity of these models. METHODS Three glioma cells lines obtained from the American Type Culture Collection (i.e., human Hs683 and U373 cells and rat C6 cells) were implanted into nude mouse brains (Hs683 and U373 cells) and rat brains (C6 cells). The astrocytic nature, as opposed to the oligodendrocytic nature, of the Hs683 and U373 models was investigated by using quantitative (computer‐assisted microscopy) immunohistochemical characterizations of nestin, vimentin, glutathione‐S‐transferase α (GSTα), GSTμ, GSTπ, and p53 expression. Comparative genomic hybridization (CGH) was employed to investigate 1p19q losses. Chronic administrations of carmustine (BCNU), fotemustin, or temozolomide were assayed in the xenografted U373 and Hs683 models. Both BCNU‐related chemotherapy and surgery were assayed in the C6 model. RESULTS The quantitative phenotypic analyses pointed to the oligodendroglial nature of the Hs683 cell line and the astrocytic nature of the U373 cell line. The Hs683 cells exhibited 1p19q losses, whereas the U373 cells did not. BCNU, fotemustin, and temozolomide dramatically increased the time of survival of the Hs683 oligodendroglioma‐bearing mice, whereas temozolomide only induced a weak but nevertheless statistically significant increase in the U373 glioma‐bearing mice. In the C6 rat glioma model, surgery and BCNU chemotherapy were more efficient than either treatment alone. CONCLUSIONS The in vivo models of gliomas of the central nervous system developed in the current work best mimicked clinical reality. They can be used either to identify new therapies against human gliomas or to optimize existing therapies. Cancer 2002;95:641–55. © 2002 American Cancer Society. DOI 10.1002/cncr.10710

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

“…However, in contrast to what has been described before (Branle et al, 2002), we could not detect deletion of 1p in this cell line (Supplementary Figure S4). Hence, Hs683 cells express PRDX1 at high transcript and protein levels.…”

“…Silencing of PRDX1 in Hs683 glioma cells leads to an increase in apoptosis The Hs683 cell line is a well-characterized glima cell line originally isolated from an oligodendroglioma (Camby et al, 2000;Belot et al, 2001;Branle et al, 2002;Hubstenberger et al, 2008). However, in contrast to what has been described before (Branle et al, 2002), we could not detect deletion of 1p in this cell line (Supplementary Figure S4).…”

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

“…Apoptosis and necrosis were determined using flow cytometry analyses of Annexin V/propidium iodide double staining, as detailed elsewhere (15,18,19,23). Experiments were performed in triplicate.…”

“…[ATP] i was measured using a bioluminescence assay (Invitrogen, Merelbeke, Belgium) in U373 GBM and A549 NSCLC cells cultured in the presence (or absence as a control) of ISP at its IC 50 concentrations (~1 μM), as detailed elsewhere (17,23). Three replicate determinations per time point were performed for each cell line.…”

“…ISP induces cytotoxic effects in human U373 GBM cells. The human U373 GBM cells resist many types of pro-apoptotic stimuli even when the pro-apoptotic compounds are analyzed at concentrations up to 10-fold the compound-related IC 50 concentrations (17,18,23). Fig.…”