A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models

<p>Abstract</p> <p>Background</p> <p>Over the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect.</p> <p>Methods</p> <p>The <it>in-vitro </it>activities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity on <it>in-vitro </it>microtubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compound <it>in vivo</it>. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours.</p> <p>Results</p> <p>In the four human and the murine glioblastoma cell lines tested, 10 μM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 × 10⁵M^-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. These <it>in vitro </it>studies were reinforced by our <it>in vivo </it>investigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB.</p> <p>Conclusion</p> <p>These <it>in vitro </it>and <it>in vivo </it>data suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model.</p

Diagnosis and predictive molecular analysis of non-small cell lung cancer in the Africa-Middle East region : challenges and strategies for improvement

The identification of tumor biomarkers provides information on the prognosis and guides the implementation of appropriate treatment in patients with many different cancer types. In nonesmall cell lung cancer (NSCLC), targeted treatment plans based on biomarker identification have already been used in the clinic. However, such predictive molecular testing is not currently a universally used practice. This is the case, in particular, in developing countries where lung cancer is increasingly prevalent. In September 2012 and November 2013, a committee of 16 lung cancer experts from Africa and the Middle East met to discuss key issues related to diagnosis and biomarker testing in NSCLC and the implementation of personalized medicine in the region. The committee identified current challenges for effective diagnosis and predictive analysis in Africa and the Middle East. Moreover, strategies to encourage the implementation of biomarker testing were discussed. A practical approach for the effective diagnosis and predictive molecular testing of NSCLC in these regions was derived. We present the key issues and recommendations arising from the meetings.Pfizer Inc.http://www.journals.elsevier.com/clinical-lung-cancer/hb201

Altérations de l'expression de la Claudine-11, ainsi que de la production et du transport du lactate dans le testicule de rat postnatal exposé in utero à un antiandrogène

L'incidence des anomalies de l'appareil reproducteur mâle, des cancers hormonodépendants et des infertilités masculines est en constante augmentation depuis plusieurs dizaine d'années. L'hypothèse a été émise qu'une exposition du foetus mâle à des composés présents dans l'environnement, capables d'interférer avec le système endocrine et dénommés perturbateurs endocriniens, serait responsable de cette augmentation. Grâce à l'utilisation d'un modèle expérimental de rat exposé in utero à l'antiandrogène flutamide, nous montrons que l'hypospermatogenèse décrite chez ces animaux à l'âge adulte pourrait résulter d'une programmation foetale par l'antiandrogène altérant la coopération fonctionnelle entre les cellules de Sertoli et les cellules germinales. En effet, des altérations de l'expression d'un gène-clé de la barrière hématotesticulaire, la claudine-11, et une inhibition de la production et du transport du lactate par les cellules de Sertoli ont été observées dans ce modèleLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Fishing for ALK with immunohistochemistry may predict response to crizotinib

Background. ALK (anaplastic lymphoma kinase) gene rearrangement is a novel oncogenic driver in non-small cell lung cancer (NSCLC) against which a selective inhibitor, namely crizotinib, is effective. Fluorescence in situ hybridization (FISH) is considered the reference method in selecting patients with ALK-positive tumors for treatment with crizotinib. Case report. We report the case of a 42-year-old non-smoking woman with an advanced pulmonary ALK FISH-negative adenocarcinoma characterized by strong immunohistochemical expression of ALK fusion protein. The patient received targeted therapy with crizotinib in compassionate use and experienced a long-lasting clinical response. Conclusion. FISH testing should not be considered the only method to select patients for therapy with ALK inhibitors and the use of multiple ALK-detecting techniques could be helpful in screening ALK-positive patients more appropriately