The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells

Thermodynamic analysis of the short-range clustering in III V solid solutions

An extension of the « D.L.P. » theory of Stringfellow taking clustering into account has been applied both to pseudobinary, pseudoternary and pseudoquaternary III V alloys. For alloys with two sites sublattices, this clustering tendency is introduced in each sublattice of the zinc blende through a positive short-range order parameter αi-j depending on temperature and composition. It is shown that clustering increases in the GaxIn 1-xX serie (X = Sb, As, P) from the antimonide (αGa-In(1/2, 700°C) = 0.04) to the phosphide (αGa-In(1/2, 700°C) = 0.08) whereas GaASyP1-y and mainly InAs yP1-y have quite random As-P distribution. For pseudoquaternaries the model predicts a linear variation of α i-j versus the composition of the other sublattice. The calculated miscibility gaps are in good agreement with known experimental results for GaxIn1- xP and GaxIn1-xAs yP1-y (the critical temperatures are respectively 750 and 880 °C), whereas the model does not explain an asymmetrical shape of miscibility gap as in the case of GaAsySb 1-y if the excess entropy reduces only to a configurational one.Une généralisation du formalisme « D.L.P. » de Stringfellow prenant en compte la tendance aux amas a éié appliquée à la fois aux alliages pseudobinaires, pseudoternaires et pseudoquaternaires III V. Pour les alliages où les sous-réseaux sont à deux sites, cette tendance est traduite, pour chaque sous-réseau de la « blende de zinc » par un paramètre d'ordre à courte distance α i-j positif, dépendant de la température et de la composition. Les valeurs obtenues pour αGa-In démontrent que, pour la série GaxIn1-xX (X = Sb, As, P), la tendance s'accroît lorsque l'on passe de Sb(α Ga-In(1/2, 700°C) = 0,04) à P (αGa-In(1/2, 700°C) = 0,08), tandis que InAsyP1-y, et dans une moindre mesure GaAsyP1 -y, comportent une répartition aléatoire des atomes As et P. Pour un pseudoquaternaire, le modèle prévoit une variation linéaire de αi-j avec la composition de l'autre sous-réseau. Les lacunes de miscibilité calculées sont en accord avec les résultats expérimentaux connus pour GaxIn1- xP et GaxIn1-xAs yP1-y : les températures critiques sont respectivement 750 °C et 880 °C. Par contre le modèle ne peut expliquer une lacune de miscibilité à forme asymétrique comme dans le cas de GaAs ySb1-y si l'entropie d'excès se réduit à une entropie de configuration

LE MODELE "D. L. P. - ORDRE-CONTRAINTE" : INFLUENCE DU DESORDRE CHIMIQUE ET DU SUBSTRAT D'EPITAXIE SUR LES DIAGRAMMES D'EQUILIBRE TERNAIRES & QUATERNAIRES I I I-V

Un nouveau modèle thermodynamique de solution solide applicable aux alliages III-V associe au modèle classique"D.L.P." l'effet d'ordre local (entropie d'excès) et l'influence stabilisatrice d'un substrat d'épitaxie (enthalpie libre d'excès due à la déformation élastique) sur les diagrammes d'équilibre ternaires et quaternaires (modèle "D.L.P.O.C."). L'introduction d'un paramètre d'ordre à courte distance dans un sous-réseau se traduit par une augmentation des températures de démixion de l'alliage (modification intrinsèque du diagramme) ; la modification extrinsèque, due à la déformation élastique du réseau épitaxié (écart paramétrique maximal Δa/asub = 10-3), explique la stabilisation d'un alliage lorsque sa composition se situe dans une lacune de miscibilité. Le modèle "D.L.P.O.C." a été appliqué aux systèmes Ga-In-P, Ga-In-As-P, Ga-As-Sb et Al-Ga-As-Sb et rend compte de manière satisfaisante de leurs diagrammes expérimentaux (équilibres liquide ⇄ solide, lacunes de miscibilité, températures critiques de démixion).A new thermodynamic model of III-V solid solutions combines the classical "D.L.P." model with two effects : 1) the effect of local order (excess entropy), 2) the stabilization effect brought about by the substrate of epitaxy (free excess enthalpy in the elastic strain case), for the calculation of ternary and quaternary phase diagram ("D.L.P.O.C." model) . Introduction of a short-range order parameter in a sub-lattice results in an increase of the phase separation temperature (intrinsec modification of the diagram) ; the extrinsec modification consequent to the elastic strain of the epitaxial lattice (lattice mismatch Δa/asub less than 10-3) explains the alloy stabilization for compositions located inside the miscibility gap. The "D.L.P.O.C." model has been used for Ga-In-P, Ga-In-As-P, Ga-As-Sb and Al-Ga-As-Sb systems. Good agreement is found with experimental data (liquid ⇄ solid equilibrium, miscibility gap, critical temperature)

Molecular dynamics in n-alkanes: Premelting phenomena and rotator phases

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Destabilizing effects of chlorine on complexes belonging to the benzene family: p-C6H4Cl2-C6F6 and p-C6H4CH3Cl-C6F6 systems

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Destabilizing effects of chlorine on complexes belonging to the benzene family: p-C6H4Cl2-C6F6 and p-C6H4CH3Cl-C6F6 systems

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Croissance épitaxique en phase liquide de GaxIn1-xp

The determination of crystallization paths in the phase diagram of Ga-In-P allows us to predict the growth condition for of homogeneous epitaxial films of GaxIn1-xP. Monocrystalline layers were obtained on (111) B oriented GaP substrates for x > 0.80 by cooling of the saturated melt. Layers of good quality have been grown on (111) B oriented GaAs substrates for 0.50 0,80 par refroidissement d'une solution saturée. Des couches de bonne qualité sur supports de GaAs orientés (111) B ont été obtenues dans le domaine de composition 0,50 < x < 0,52 par une méthode verticale de croissance épitaxique en phase liquide à température constante. Les spectres de luminescence caractéristiques de ces dépôts sont présentés

Destabilizing effects of chlorine on complexes belonging to the benzene family: p-C6H4Cl2-C6F6 and p-C6H4CH3Cl-C6F6 systems

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Cooperativity in a spin transition ferrous polymer: Interacting domain model, thermodynamic, optical and EPR study

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