Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

YesThe membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP family, demonstrate widespread expression in multiple tumor types, and play key roles in cancer growth, migration, invasion and metastasis. Despite a large body of published research, relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer. This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue, summarises the evidence for roles in prostate cancer progression, and examines the data relating to MT-MMP function in the development of bone metastases. Finally, the therapeutic potential of targeting MT-MMPs is considered. While MT-MMP inhibition presents a significant challenge, utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity

Anti-colorectal cancer activity of an organometallic osmium arene azopyridine complex

This first in vivo antitumour activity for an organometallic osmium arene complex, [Os(eta(6)-p-cym)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF(6), is reported. The complex delays the growth of HCT116 human colon cancer xenografts in mice, with negligible toxicity. Its activity appears to involve redox mechanisms and its potency towards A2780 ovarian and A549 lung cancer cells is increased significantly in combination with L-buthionine-sulfoximine

Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass

YesObjective The hypothesis that sleeve gastrectomy (SG) is not associated with an increase in mucosal colorectal cancer (CRC) biomarkers, unlike Roux-en-Y gastric bypass (RYGB), was tested. Design and Methods Rectal mucosa, blood, and urine were obtained from morbidly obese patients (n = 23) before and after (median 28 months) SG, as well as from nonobese controls (n = 20). Rectal epithelial cell mitosis and apoptosis, crypt size/fission, and pro-inflammatory gene expression were measured, as well as systemic inflammatory biomarkers, including C-reactive protein (CRP). Results The mean pre-operative body mass index in SG patients was 65.7 kg/m2 (24.7 kg/m2 in controls). Mean excess weight loss post-SG was 38.2%. There was a significant increase in mitosis frequency, crypt size, and crypt fission (all P < 0.01) in SG patients versus controls, as well as evidence of a chronic inflammatory state (raised CRP and mononuclear cell p65 NFκB binding), but there was no significant change in these biomarkers after SG, except CRP reduction. Macrophage migration inhibitory factor mRNA levels were increased by 39% post-SG (P = 0.038). Conclusions Mucosal biomarkers of CRC risk do not increase at 6 months following SG, unlike RYGB. Biomarkers of rectal crypt proliferation and systemic inflammation are increased in morbidly obese patients compared with controls

Drug delivery in a tumour cord model: a computational simulation

YesThe tumour vasculature and microenvironment is complex and heterogeneous, contributing to reduced delivery of cancer drugs to the tumour. We have developed an in silico model of drug transport in a tumour cord to explore the effect of different drug regimes over a 72 h period and how changes in pharmacokinetic parameters affect tumour exposure to the cytotoxic drug doxorubicin. We used the model to describe the radial and axial distribution of drug in the tumour cord as a function of changes in the transport rate across the cell membrane, blood vessel and intercellular permeability, flow rate, and the binding and unbinding ratio of drug within the cancer cells. We explored how changes in these parameters may affect cellular exposure to drug. The model demonstrates the extent to which distance from the supplying vessel influences drug levels and the effect of dosing schedule in relation to saturation of drug-binding sites. It also shows the likely impact on drug distribution of the aberrant vasculature seen within tumours. The model can be adapted for other drugs and extended to include other parameters. The analysis confirms that computational models can play a role in understanding novel cancer therapies to optimize drug administration and delivery

The synthesis and properties of some pyrido [1, 2-a] Pyrazinum Salts

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Mathematical and computational models of drug transport in tumours

The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a ‘tumour cord’ geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are ‘pharmacokinetically resistant’ to chemotherapeutic strategies

Saskatchewan health stakeholders and the 1991-96 wellnesss program

Powerful, entrenched health care stakeholders played a major role in limiting the health reform initiative of the Government of Saskatchewan in the 1990s. The politics of the decade was dominated by the fiscal crisis which prompted the government to embark on health care reform at the same times as it limited the scope of the reform. The narrative of Saskatchewan’s health reform efforts showed that the government focused on the politics of health care, specifically the need to manage the diverse and often competing interests of health care stakeholders. It also reveals the dynamic between the stakeholders, the press and public opinion. As health stakeholders expressed their concerns about health care reform, the press and the public became more critical and the government backed away from its commitment to health reform