Vandetanib for the Treatment of Metastatic Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) represents an aggressive form of thyroid malignancy. Some may occur spontaneously or can be associated with Multiple Endocrine Neoplasia syndromes, or Familial Medullary Thyroid Cancer syndrome. In these patients, the protooncogene RET (rearranged during transfection) is mutated. In patients who have unresectable or metastatic disease, the long term prognosis is poor. New treatments for this disease have focused on the use of targeted agents that inhibit the receptor tyrosine kinase of RET. One of these treatments, Vandetanib (Caprelsa, Astra Zeneca), recently has received approval from the Food and Drug Administration for the treatment of patients with progressive locally advanced and/or metastatic disease. This review highlights the studies that led to the drug’s approval, and discusses on the potential financial costs of treatment and side effects of this therapy. The main clinical studies evaluating Vandetanib for the treatment of other solid tumors will also be reviewed

Capturing complex tumour biology in vitro: Histological and molecular characterisation of precision cut slices

Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1α. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means

Mechanism of action of polymer-anthracyclines Potential to overcome multidrug resistance

SIGLEAvailable from British Library Document Supply Centre- DSC:DX96472 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer

In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation

Vascular Endothelial Growth Factor Inhibits Bone Morphogenetic Protein 2 Expression in Rat Mesenchymal Stem Cells

Introduction: While several studies report that bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) can act synergistically to improve bone tissue engineering, others suggest that VEGF inhibits osteogenesis. The purpose of these experiments was therefore to evaluate the effect of dual transfection of these growth factors and potential mechanisms of interaction on gene expression and osteogenesis in vitro and in vivo. Methods: Marrow-derived mesenchymal stem cells (MSCs) were exposed to recombinant VEGF protein or transfected with adenoviruses encoding BMP2, VEGF, or LacZ in a variety of ratios. Alterations in gene and protein expression in vitro as well as bone formation in vivo were assessed. Results: MSC exposure to AdV-VEGF or recombinant VEGF inhibited BMP2 mRNA expression, protein production, and MSC differentiation. Coculture experiments revealed that BMP2 suppression occurs through both an autocrine and a paracrine mechanism, occurring at the transcriptional level. Compared to controls, cotransfection of VEGF and BMP2 transgenes prevented ectopic bone formation in vivo. Conclusion: VEGF is a potent inhibitor of BMP2 expression in MSCs, and supplementation or overexpression of VEGF inhibits osteogenesis in vitro and ectopic bone formation in vivo. Strategies to utilize MSCs in bone tissue engineering therefore require careful optimization and precise delivery of growth factors for maximal bone formation