Glutathione <em>S</em>-transferase P1 (<em>GSTP1</em>) directly influences platinum drug chemosensitivity in ovarian tumour cell lines

BACKGROUND: Chemotherapy response in ovarian cancer patients is frequently compromised by drug resistance, possibly due to altered drug metabolism. Platinum drugs are metabolised by glutathione S-transferase P1 (GSTP1), which is abundantly, but variably expressed in ovarian tumours. We have created novel ovarian tumour cell line models to investigate the extent to which differential GSTP1 expression influences chemosensitivity. METHODS: Glutathione S-transferase P1 was stably deleted in A2780 and expression significantly reduced in cisplatin-resistant A2780DPP cells using Mission shRNA constructs, and MTT assays used to compare chemosensitivity to chemotherapy drugs used to treat ovarian cancer. Differentially expressed genes in GSTP1 knockdown cells were identified by Illumina HT-12 expression arrays and qRT–PCR analysis, and altered pathways predicted by MetaCore (GeneGo) analysis. Cell cycle changes were assessed by FACS analysis of PI-labelled cells and invasion and migration compared in quantitative Boyden chamber-based assays. RESULTS: Glutathione S-transferase P1 knockdown selectively influenced cisplatin and carboplatin chemosensitivity (2.3- and 4.83-fold change in IC(50), respectively). Cell cycle progression was unaffected, but cell invasion and migration was significantly reduced. We identified several novel GSTP1 target genes and candidate platinum chemotherapy response biomarkers. CONCLUSIONS: Glutathione S-transferase P1 has an important role in cisplatin and carboplatin metabolism in ovarian cancer cells. Inter-tumour differences in GSTP1 expression may therefore influence response to platinum-based chemotherapy in ovarian cancer patients

RAFT polymerization in bulk and emulsion

Detailed models of the RAFT polymerization in both non-segregated (bulk) and segregated (seeded emulsion) systems are presented. it is shown that satisfactory agreements between experiments and models can be achieved, and that effects such as inhibition and retardation, or the polymerization behavior at high conversions can be readily explained. in all cases the model parameter fitting has been minimized, being mostly limited to the rate coefficients of the addition/fragmentation reactions in the RAFT polymerization. Therefore, such models are believed to be invaluable tools towards a deeper understanding of the main phenomena underlying RAFT polymerization

Biomarkers indicate mixture toxicities of fluorene and phenanthrene with endosulfan toward earthworm (Eisenia fetida)

alpha-Endosulfan and some polycyclic aromatic compounds (PAHs) are persistent in the environment and can reach crop products via contaminated agricultural soils. They may even be present as mixtures in the soil and induce mixture toxicity in soil organisms such as earthworms. In this study, the combined toxicities of PAHs with alpha-endosulfan were determined in Eisenia fetida adults using an artificial soil system. alpha-Endosulfan and five PAHs were tested for their acute toxicity toward E. fetida in artificial soils. Only alpha-endosulfan, fluorene, and phenanthrene showed acute toxicities, with LC50 values of 9.7, 133.2, and 86.2 mg kg(-1), respectively. A mixture toxicity assay was conducted using alpha-endosulfan at LC10 and fluorene or phenanthrene at LC50 in the artificial soils. Upon exposure to the mixture of fluorene and alpha-endosulfan, earthworms were killed in increasing numbers owing to their synergistic effects, while no other mixture showed any additional toxicity toward the earthworms. Along with the acute toxicity results, the biochemical and molecular changes in the fluorene- and phenanthrene-treated earthworms with or without alpha-endosulfan treatment demonstrated that enhancement of glutathione S-transferase activity was dependent on the addition of PAH chemicals, and the HSP70 gene expression increased with the addition of alpha-endosulfan. Taken together, these findings contribute toward understanding the adverse effects of pollutants when present separately or in combination with other types of chemicals.ope