In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

Abstract

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.

Efficacy of vincristine administered via convection-enhanced delivery in a rodent brainstem tumor model documented by bioluminescence imaging

“…These rats were euthanized with CO 2 at 1, 3,5,7,9,11,13,15,17, and 18 days postinoculation. BLI was measured prior to euthanization.…”

“…To address the accuracy of quantitative BLI as an indicator of brainstem tumor size, C6-Luc cells were inoculated into ten untreated rats and tumor size assayed by photon emission and histopathological measurement in individual animals at 1, 3,5,7,9,11,13,15,17, and 18 days following inoculation. On each day, one rat was imaged with BLI and then euthanized to calculate histopathological tumor size.…”

“…Vincristine (VCR) was chosen for this investigation because it has demonstrated efficacy against human glioma cells in vitro [7,8]. Although VCR can induce neurotoxicity [9,10], it was deemed well tolerated at low dosage for normal rat brain via intracerebral injection [11] and safe for conjunction treatment of human high-grade gliomas intravenously (I.V.)…”

Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis

“…In order to overcome resistance, both chemotherapeutic and biological agents have been used with success to sensitize tumor cells to TRAIL-mediated apoptosis. 9,10 Sensitization effects are suggested to occur by potentiation of the mitochiondrial apoptotic Previous studies in mesothelioma, prostate and glioma cells have shown that treatment with the protein synthesis inhibitor anisomycin can increase the sensitivity to TRAIL induced apoptosis. [12][13][14] Anisomycin binds the 60S ribosomal subunit and block peptide bond formation and DNA synthesis.…”

Efficacy of interstitial continuous vincristine infusion in a bioluminescent rodent intracranial tumor model

“…BLI was used to monitor tumor growth and chemotherapeutic efficacy. VIN is effective against human glioma cells in vitro [28,29], and its physical properties make it a potentially good candidate for intratumoral glioma treatment. Unfortunately, its clinical effectiveness has been limited by the BBB, but as this molecule is water-soluble, direct administration to the tumor via i.c.…”