In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively prescribed antimetabolite, 5-fluorouracil (5-FU). In this study, we tried to reverse 5-FU resistance by using a double-punch strategy: combining 5-FU with a biochemical modulator to improve its tumoural activation and encapsulating both these agents in one same stealth liposome. Experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a up to 80% sensitisation to 5-FU when these cells were treated with our liposomal formulation. Results with this formulation demonstrated 30% higher tumoural drug uptake, better activation with increased active metabolites including critical-5-fluoro-2-deoxyuridine-5-monophosphate, superior inhibition (98%) of tumour thymidylate synthase, and subsequently, higher induction of both early and late apoptosis. Drug monitoring showed that higher and sustained exposure was achieved in rats treated with liposomal formulation. When examined in a xenograft animal model, our dual-agent liposomal formulation caused a 74% reduction in tumour size with a mean doubling in survival time, whereas standard 5-FU failed to exhibit significant antiproliferative activity as well as to increase the lifespan of tumour-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoural activation and the use of an encapsulated formulation

Harnessing tumor immunity with cytotoxics: T cells monitoring in mice bearing lung tumors treated with anti-VEGF and pemetrexed-cisplatin doublet

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Carotenoid Diversity in Cultivated Citrus Is Highly Influenced by Genetic Factors

Publication Inra prise en compte dans l'analyse bibliométrique des publications scientifiques mondiales sur les Fruits, les Légumes et la Pomme de terre. Période 2000-2012. http://prodinra.inra.fr/record/256699International audienceCitrus fruits are complex sources of carotenoids with more than 100 kinds of pigments reported in this genus. To understand the origin of the diversity of carotenoid compositions of citrus fruit, 25 genotypes that belong to the 8 cultivated Citrus species were analyzed. Juice extracts of mature fruit were analyzed by high-performance liquid chromatography using a C-30 column. The 25 citrus genotypes presented different carotenoid profiles with 25 distinct compounds isolated. Statistical analyses revealed a strong impact of genotype on carotenoid compositions. Two kinds of classifications of genotypes were performed: on qualitative data and on quantitative data, respectively. The results showed that variability in carotenoid compositions was more interspecific than intraspecific. Two carotenoids, cis-violaxanthin and the beta-cryptoxanthin, strongly determined the classification on qualitative data, which was also in agreement with previous citrus variety classifications. These findings provide evidence that, as for other phenotypical traits, the general evolution of cultivated Citrus is the main factor of the organization of carotenoid diversity among citrus varieties. To the authors' knowledge this is the first study that links the diversity of carotenoid composition to the citrus genetic diversity. These results lead to the proposed major biosynthetic steps involved in the differential carotenoid accumulation. Possible regulation mechanisms are also discussed

Lethal toxicity after administration of azacytidine:implication of the cytidine deaminase-deficiency syndrome.

International audienceAzacytidine, an antimetabolite with an original epigenetic mechanism of action, increases survival in patients diagnosed with high-risk myelodysplasic syndromes or acute myeloid leukemia with less than 30% medullar blasts. Azacytidine is a pyrimidine derivative that undergoes metabolic detoxification driven by cytidine deaminase (CDA), a liver enzyme whose gene is prone to genetic polymorphism, leading to erratic activity among patients. Clinical reports have shown that patients with the poor metabolizer (PM) phenotype are likely to experience early severe or lethal toxicities when treated with nucleosidic analogs such as gemcitabine or cytarabine. No clinical data have been available thus far on the relationships between CDA PM status and toxicities in azacytidine-treated patients. Here, we measured CDA activity in a case of severe toxicities with fatal outcome in a patient undergoing standard azacytidine treatment. Results showed that the patient was PM (i.e. residual activity reduced by 63%), thus suggesting that an impaired detoxification step could have given rise to the lethal toxicities observed. This case report calls for further prospective studies investigating the exact role that CDA status plays in the clinical outcome of patients treated with azacytidine

Impact of a low water input, genotype and process on the texture of purees from two tomato cultivars

International audienceThe viscosity of tomato puree is a primary parameter for the industry which can be modified by changing processing methods or by using adapted cultivars known for their ability to produce viscous puree. Differences in viscosity are also observed between production years and irrigation levels, due to their influence on fruit composition. To our knowledge, there is no documentation of the detailed mechanisms involved when texture changes due to the effects of genotypes, processes or growing conditions. In this study we present the results obtained with purees from two different genotypes, two irrigation treatments and two processes (hot- or cold-break) during two years. Their viscosity was regarded according to their soluble solid and total dry matter content, the particles sizes distribution, and serum viscosity. A partial least square discriminant analysis (PLS-DA) of the collected data indicates that various mechanisms occurred when viscosity changed between cultivars and process. The growing conditions had an impact, but did not change the ranking of samples obtain according to the two former effects

Yin and yang of cytidine deaminase roles in clinical response to azacitidine in the elderly: a pharmacogenetics tale.

International audienceAzacitidine is a mainstay for treating hematological disorders. Azacitidine is metabolized by cytidine deaminase, coded by a highly polymorphic gene. Here, we present two elderly patients with opposite clinical outcomes after azacitidine treatment. First, an acute myeloid leukemia patient showed life-threatening toxicities, but outstanding complete remission, after a single round of azacitidine. Further investigations showed that this patient was cytidine deaminase 79A>C (rs2072671) homozygous with a marked deficient phenotype. Next, a chronic myelomonocytic leukemia patient displayed complete lack of response despite several cycles of azacitidine. This patient had a rapid-deaminator phenotype linked to the -31delC deletion (rs3215400). These polymorphisms lead to opposite clinical outcomes in patients with myelodysplastic syndromes treated with azacitidine, thus suggesting that determining cytidine deaminase status could help to forecast clinical outcome

Response to trametinib of histiocytosis with an activating PTPN11 mutation

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