The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma.
ABSTRACT First line treatment of metastatic melanoma includes the methylating agent dacarbazine or its analogue temozolomide (TMZ) with improved pharmacokinetics and tolerability. However, the prognosis of the metastatic disease is poor and several trials are evaluating TMZ in polychemotherapy protocols. The novel glutathione transferase P1-1 (GSTP1-1) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has recently shown activity against melanoma through c-Jun N-terminal kinase activation. In this study we have investigated the in vitro and in vivo efficacy of NBDHEX and TMZ combination against melanoma. The results indicated that NBDHEX and TMZ exerted in vitro synergistic anti-proliferative effects in murine B16 and human A375 melanoma cells. In B16 cells TMZ as single agent caused cell accumulation at the G(2)/M phase of cell cycle, whereas NBDHEX induced mainly apoptotic effects. NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a more than additive increase of p53 activation. The in vivo efficacy of NBDHEX and TMZ has been investigated in an orthotopic B16 model. Treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased tumour growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D1 and CD31 in all treatment groups; VEGF expression was, instead, markedly decreased only in NBDHEX or NBDHEX and TMZ treated samples. These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma.
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ABSTRACT: A large database including temporal trends of physical, ecological and socio-economic data was developed within the EUROCAT project. The aim was to estimate the nutrient fluxes for different socio-economic scenarios at catchment and coastal zone level of the Po catchment (Northern Italy) with reference to the Water Quality Objectives reported in the Water Framework Directive (WFD 2000/60/CE) and also in Italian legislation. Emission data derived from different sources at national, regional and local levels are referred to point and non-point sources. While non-point (diffuse) sources are simply integrated into the nutrient flux model, point sources are irregularly distributed. Intensive farming activity in the Po valley is one of the main Pressure factors Driving groundwater pollution in the catchment, therefore understanding the spatial variability of groundwater nitrate concentrations is a critical issue to be considered in developing a Water Quality Management Plan. In order to use the scattered point source data as input in our biogeochemical and transport models, it was necessary to predict their values and associated uncertainty at unsampled locations. This study reports the spatial distribution and uncertainty of groundwater nitrate concentration at a test site of the Po watershed using a probabilistic approach. Our approach was based on geostatistical sequential Gaussian simulation used to yield a series of stochastic images characterized by equally probable spatial distributions of the nitrate concentration across the area. Post-processing of many simulations allowed the mapping of contaminated and uncontaminated areas and provided a model for the uncertainty in the spatial distribution of nitrate concentrations.Environmental Pollution 03/2005; 133(3):569-80. · 3.73 Impact Factor
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ABSTRACT: In many European lowland rivers and riparian floodplains diffuse nutrient pollution is causing a major risk for the surface waters and groundwater to not achieve a good status as demanded by the European Water Framework Directive. In order to delimit the impact of diffuse nutrient pollution substantial and often controversial changes in landuse and management are under discussion. In this study we investigate the impact of two complex scenarios considering changes in landuse and land management practices on the nitrate loads of a typical lowland stream and the riparian groundwater in the North German Plains. Therefore the impacts of both scenarios on the nitrate dynamics, the attenuation efficiency and the nitrate exchange between groundwater and surface water were investigated for a 998.1 km(2) riparian floodplain of the Lower and Central Havel River and compared with the current conditions. Both scenarios target a substantial improvement of the ecological conditions and the water quality in the research area but promote different typical riparian landscape functions and consider a different grade of economical and legal feasibility of the proposed measures. Scenario 1 focuses on the optimisation of conservation measures for all natural resources of the riparian floodplain, scenario 2 considers measures in order to restore a good status of the water bodies mainly. The IWAN model was setup for the simulation of water balance and nitrate dynamics of the floodplain for a perennial simulation period of the current landuse and management conditions and of the scenario assumptions. The proposed landuse and management changes result in reduced rates of nitrate leaching from the root zone into the riparian groundwater (85% for scenario 1, 43% for scenario 2). The net contributions of nitrate from the floodplain can be reduced substantially for both scenarios. In case of scenario 2 a decrease by 70% can be obtained. For scenario 1 the nitrate exfiltration rates to the river drop even below the infiltration rates from the river, the riparian floodplain in that scenario represents a net sink for river derived nitrate. As the nitrate contributions from the investigated riparian floodplain represent only a small proportion of the total nitrate loads within the river (1% p.a.) the overall impact of the scenario measures on the nitrate loads at the river outlet remains small. However, during the ecologically most sensitive summer periods under current conditions nitrate contributions from the riparian groundwater of the Lower and Central Havel River (which covers only 5% of the area of the Havel catchment) represent more than 20% of the river loads. By the implementation of the investigated landuse changes within the research area the groundwater derived nitrate contributions could be halved to only 10% during summer baseflow conditions.Science of The Total Environment 02/2008; 389(1):149-64. · 3.26 Impact Factor
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ABSTRACT: and use and urban activity in the catchment of the Scheldt river system have deeply changed during the last 50years, modifying in turn the water quality of the drainage network and the fluxes of nutrient transferred to the estuary and to the sea. Based on the RIVERSTRAHLER model, developed for establishing the link between the biogeochemical functioning of large river systems and the constraints set by the meteorology, the morphology of the drainage network and the human activity in the watershed, we reassembled the data available to document these constraints in the Scheldt basin since the last half of the XXth century and we used them to reconstruct the variations of nutrient and oxygen concentrations at the outlet of the Scheldt drainage network. We compared the results with the water quality data at the entrance of the estuarine zone available since the 1960s. Both model results and observational data show a very severe deterioration of water quality (with deep oxygen depletion) in the beginning of the 1960s, while a clear trend to improvement is apparent since the late 1980s. The budget of nutrient loadings from the watershed, retention within the drainage network and delivery to the estuarine zone is established on an annual basis for the 50 last years. The yearly fluxes of nutrient delivered by the river to the estuary and the sea show a severe depletion of silica with respect to nitrogen compared with the requirements of diatoms, and a clear shift from the early 1990s from nitrogen to phosphorus potential limitation. Seasonal variations of nutrient delivery are however much more pronounced for nitrogen, with much less inputs during the dry seasons, while phosphorus inputs, mainly from point sources are more constant, so that nitrogen limitation can still occur during summer. Compared with similar budget estimations carried out for the Seine river system, the Scheldt basin, in spite of its much higher population density, does not deliver higher specific fluxes of nutrient (presently about 2000 kgN/km2/yr, 80 kgP/km2/yr and 1000 kgSi/km2/yr), owing to very efficient processes of nutrient retention.Hydrobiologia 04/2005; 540(1):47-67. · 1.99 Impact Factor