Surgery (RMH) - Research Publications
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ItemIn vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs(NATURE PUBLISHING GROUP, 2008-07-15)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.
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ItemEditorial(Elsevier, 1994-01-01)
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ItemEVALUATION OF TUMOR AND TISSUE DISTRIBUTION OF PORPHYRINS FOR USE IN PHOTODYNAMIC THERAPY(CHURCHILL LIVINGSTONE, 1992-03)A range of pure, monomeric porphyrins were synthesised and their localising capacities compared to HpD and Hp at 6 h and 24 h post injection in the mouse C6 intracerebral glioma model as well as in normal brain, skin, muscle, kidney, spleen, liver, lung and whole blood. The partition coefficients were examined between PBS and 2-octanol over the pH range 7.4-6.6 and pH profiles were established. A parabolic relationship was observed between log (porphyrin tumour concentration) at pH 7.4, with maximal tumour localisation at log (partition coefficient), pi, of approximately zero. Porphyrins with side chains with nett cationic character also exhibited up upward (parabolic) dependence on pi for most tissues studied, with maximal porphyrin localisation at pi of 0-0.5. In contrast, those porphyrins with nett anionic character exhibited a downward (negative) parabolic trend for all eight tissues studied, with minimal porphyrin localisation at pi of approximately zero. Four porphyrins (4, 11, 12, 13) exhibited similar or better tumour localisation than HpD, and two (11 and 12) offer promise as lead compounds for the design of improved porphyrins for use in PDT.
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ItemEVALUATION OF A MORPHOLINOTHIOLPORPHYRIN FOR USE IN PHOTODYNAMIC THERAPY(STOCKTON PRESS, 1994-09)The photonecrotic effectiveness of a morpholinothiolporphyrin derived from haematoporphyrin was measured in an animal model of cerebral glioma. The dose administered was 20 mg kg-1 and the laser dose varied from 0 to 200 J cm-2. The tumour necrosis was at least as good as that of HpD, and this therapeutic response may be attributed to the targeting of specific 'photopotent' subcellular sites.
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ItemEvaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma(NATURE PUBLISHING GROUP, 1996-02)A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.
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ItemOVEREXPRESSION OF MULTIPLE ONCOGENES RELATED TO HISTOLOGICAL GRADE OF ASTROCYTIC GLIOMA(CHURCHILL LIVINGSTONE, 1992-07)The expression of the c-erbB-1, c-myc, Ha/N-ras and c-fos oncogenes was investigated in 62 astrocytomas of low, intermediate and high grades by immunogold silver histochemistry. Elevated expression of c-erbB-1 was observed in 95%, 48% and 86% of low, intermediate and high grade tumours respectively, c-myc in 5%, 33% and 76% respectively, Ha/N-ras in 0, 43% and 71% respectively and c-fos in 55%, 48% and 52% respectively. Controls included normal brain and tumour sections immunoreacted with pre-immune serum or with antisera absorbed with synthetic peptides. Analysis of co-overexpression revealed that low grade tumours co-overexpressed a maximum of two of these genes, intermediate grade tumours a maximum of three of these genes, while co-overexpression of all four genes was observed in some high grade tumours. Co-overexpression of c-erbB-1 and c-fos was frequently observed in low grade astrocytomas and may be predictive of non-progression. On the other hand, there was a statistically significant increase in the number of tumours overexpressing Ha/N-ras or c-myc with increasing grade of tumour, suggesting that overexpression of these two oncogenes may be indicative of progression.