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P-glycoprotein belongs to the ATP binding cassette transporters, responsible for the multidrug resistance of cancer cells. These transporters efflux hydrophobic drugs outside cells and decrease their therapeutic efficacy. The aim of this study was to investigate the effect of vandetanib, an oral tyrosine kinase inhibitor of EGFR, VEGFR 2 and RET kinases, on the functionality of P-gp after a 24 h-treatment at therapeutic concentration (2 μM), and its ability to increase the cytotoxicity of chemotherapeutic agents in multidrug resistance cancer cells. In this study we found that IGROV1-DXR and IGROV1-CDDP cells were resistant to doxorubicin and cisplatin respectively, compare to parental cell line IGROV1. The parental sensitive and the two resistant cell lines similarly expressed MRP1 and did not express BCRP. Moreover, in contrast to the IGROV1 and IGROV1-CDDP cells, IGROV1-DXR cell line overexpressed P-gp. Functional activity studies demonstrated that MRP1 was not functional and the MDR phenotype in IGROV1-DXR cells was linked to P-gp functionality. Results also showed that vandetanib reversed resistance to doxorubicin in IGROV1-DXR cells, but not to cisplatin in IGROV1-CDDP cells. After 24 h of treatment, vandetanib increased the accumulation of rhodamine 123 and calcein AM, demonstrating a functional inhibition of the transporter. In IGROV1-DXR cell line, vandetanib reverse resistance to doxorubicin by inhibiting the functionality of P-gp. In conclusion, vandetanib should be an option for drug combination in patients already developing a P-gp mediated multidrug resistance.

Resume Bien que l’incidence du cancer soit en augmentation, les traitements anticancereux sont devenus plus efficaces, avec pour resultat, un accroissement du nombre de femmes survivantes, soumises aux consequences a long terme de la chimiotherapie. Un des principaux effets indesirables des traitements anti-cancereux indesirables est represente par l’insuffisance ovarienne prematuree. Ainsi, les jeunes femmes soumises a ce type de traitement sont demandeuses d’une preservation de leur fertilite. Classiquement, la cryopreservation embryonnaire et/ou ovocytaire apres stimulation ovarienne, represente la technique de reference, offrant les meilleurs resultats. Cependant, nombreuses sont les patientes chez qui la stimulation ovarienne n’est pas realisable, faute de temps ou en raison d’une pathologie sous-jacente estrogenodependante. Pour ces patientes, la technique de maturation ovocytaire in vitro (MIV) a ete proposee, permettant un recueil ovocytaire immediat, sans stimulation par les gonadotrophines exogenes, independamment de la phase du cycle. Par ailleurs, elle est utilisable en combinaison avec la cryopreservation de tissu ovarien. Dans cette revue, nous discuterons de la place de la MIV dans la preservation de la fertilite de la femme jeune.

N-myc oncogene amplification is one of the most established prognostic factors in neuroblastoma (NB), a young children solid tumor. Amounts of ferritin, an iron storage protein, are abnormally increased in serum of patients with advanced stage disease. N-myc amplified NB cells can synthesize zinc metalloenzymes allowing tumor invasion and metastases formation. The aim of this study was to find a relationship between N-myc amplification and trace metals in human neuroblasts. Coupling PIXE and RBS techniques, nuclear microprobe allowed to analyze elemental distributions and to determine trace metal concentrations within cultured neuroblasts characterized by various degrees of N-myc amplification. They were compared to trace metal distributions and concentrations in tumor xenograft models of human NB, after injection of cells from the same lines in athymic nude mice. Our data allowed to establish a relation between trace metal contents and mechanisms of NB oncogenesis, amplified cell lines representing more aggressive phenotypes of the disease. They should be confirmed by analysis of cultured neuroblasts and tumors issued from a non-amplified cell line transfected with the N-myc oncogene.

N- myc oncogene amplification is a powerful predictor of aggressive behavior of neuroblastoma (NB), the most common solid tumor of the early childhood. Since N- myc overexpression – subsequent to amplification – determines a phenotype of invasiveness and metastatic spreading, it is assumed that N- myc amplified neuroblasts synthesize zinc metalloenzymes leading to tumor invasion and formation of metastases. In order to test a possible relation between N- myc oncogene amplification and trace metal contents in human NB cells, Fe, Cu and Zn concentrations have been measured by nuclear microprobe analysis in three human neuroblastoma cell lines with various degrees of N- myc amplification. Elemental determinations show uniform distribution of trace metals within the cells, but variations of intracellular trace metal concentrations with respect to the degree of N- myc amplification are highly dependent on the nature of the element. Zinc concentration is higher in both N- myc amplified cell lines (IMR-32 and IGR-N-91) than in the non-amplified cells (SK–N–SH). In contrast, intracellular iron content is particularly low in N- myc amplified cell lines. Moreover, copper concentrations showed an increase with the degree of N- myc amplification. These results indicate that a relationship exists between intracellular trace metals and N- myc oncogene amplification. They further suggest that trace metals very probably play a determinant role in mechanisms of the neuroblastoma invasiveness.

Some transition metals play important regulatory roles in gene expression. The disturbance of their cellular levels could be involved in oncogene expression and tumorigenesis. Nuclear Microprobe Analysis (NMPA) was used to measure cellular trace metal levels (Mn, Fe, Cu, Zn) in two human neuroblastoma cell lines characterized by distinct genotypes. In this paper, a specific protocol established for sample preparation of neuronal cultured cells is described. Trace metal concentrations in SK-N-SH and IGR-N-91 cells exhibiting respectively a single copy, and 60 copies, of the N-myc oncogene are reported. A brief discussion on experiment design for NMPA of trace metal functions in gene expression is also presented.

Macro-and Micro-PIXE analysis were applied to study the mechanisms of cellular resistance to cisplatin, a chemotherapeutic agent, widely used nowadays for the treatment of ovarian cancer. Two cultured cell lines, a cisplatin-sensitive and a resistant one, were compared for their trace elements content and platinum accumulation following in vitro exposure to the drug. Bulk analysis revealed significant differences in copper and iron content between the two lines. Subsequent individual cell microanalysis permitted us to characterize the response of the different morphological cell types of the resistant line. This study showed that the metabolism of some trace metals in cisplatin-resistant cells could be affected but the exact relationship with the resistant phenotype remains to be determined. From a technical point of view, this experiment demonstrated that an accurate measurement of trace elements could be derived from nuclear microprobe analysis of individual cell.

Auteur(s) : J Benard Un caractere fondamental de la cellule carcinomateuse est son independance d’ancrage, autrement dit sa capacite a survivre en absence de matrice extracellulaire (MEC), la structure composee de l’ensemble de macromolecules secretees par la membrane basale d’un epithelium. En revanche, dans les memes conditions, la cellule normale connait un phenomene d’anoikis ou mort cellulaire par perte d’ancrage via un processus apoptotique caspase-dependant ou via [...]

The thermodynamics properties of some metallic 2D sulphides and 3D sulphides are presented in the shape of diagram following Ellingham's model. For sulphur adsorption the quantities at saturation (Γ sat s ) are collected on several metals as well as the ranges of stability in temperature and pressure. A close correlation exists between the heats of formation of 2D and 3D compounds.

The paper studies the second best solution of an optimal taxation problem, when some prices are subject to exogenous constraints. We show that, under specific conditions upon preferences and technology, the signs of optimal taxes can be deduced from the signs of cross price elasticities. The conditions can be related to a special form of separability (‘Morishima separability’), which fits reasonably well to a number of national consumption structures.

Resume L'etude de l'autodiffusion des ions dans les halogenures alcalins polycristallins constitues de grains de differentes grosseurs a ete realisee en fonction de la temperature. Dans tous les cas, l'energie d'activation d'autodiffusion des ions est la meme, que la migration s'effectue dans des monocristaux ou dans des polycristaux. Dans tous les composes, a l'exclusion des sels de cesium, la vitesse de diffusion du cation est la meme, que l'on opere sur des mono-ou des polycristaux; par contre, celle de l'anion s'accroit et cet accroissement est d'autant plus important que la dimension moyenne des cristaux constituant les agregats polycristallins est plus petite. Cependant, dans le cas des sels de cesium, la vitesse de diffusion du cation est egalement influencee par la presence des surfaces intercristallines. Il est possible de relier cet accroissement de vitesse de diffusion a la polarisation des ions. Plus l'ion est polarise, plus l'influence des surfaces intercristallines est importante et ceci quelle que soit la polarite de l'ion diffusant. Une etude autoradiographique confirme ces resultats.

Resume Une analyse prealable est faite du processus de striation reversible des metaux dans ses rapports avec l'attaque thermique consideree dans sa forme la plus generale. Le diagramme de striation reversible du fer dans des atmospheres H 2 -H 2 O est etabli en fonction de la temperature et de la composition de l'atmosphere. On examine les possibilites de generalisation aux atmospheres sulfurantes et aux surfaces intercristallines.