Issue 3 2010

High content cell based primary screening for oncology targets – a perspective

Issue 3 2010 / 25 June 2010 / Peter Alcock, Colin Bath, Carolyn Blackett & Peter B. Simpson, Screening & Assay Sciences, Cancer Bioscience, AstraZeneca Alderley Park

Over the last 15 years, vendors have offered microscope-based instruments capable of producing images of fluorescent labelled components of cells grown in microtitre plates. These instruments are typically bundled with analysis software capable of defining the relative distribution of several fluorescent markers on a cell by cell basis1,2. As the readers have improved and image acquisition and analysis times have reduced, the potential for screening larger compound libraries has presented itself. High Content Screening (HCS) i.e. the generation of multiparameter data from a single well, has thus become an important tool in the High-Throughput Screening (HTS) laboratory. (more…)

Tagged with: AstraZeneca, Cancer Biology, Carolyn Blackett, Colin Bath, GPCRs, HCA (High Content Analysis), HCS (High Content Screening), HTS (High Throughput Screening), Peter Alcock, Peter B. Simpson

Article 3: The implementation of rapid microbiological methods

Issue 3 2010 / 24 June 2010 / Michael J. Miller, Ph.D., President, Microbiology Consultants, LLC

This is the third in a series of articles on rapid microbiological methods that will appear in European Pharmaceutical Review during 2010. Rapid microbiological methods (RMMs) have been implemented by a number of companies around the world. In some cases, it is necessary to work with regulatory authorities in order to effectively introduce a RMM in place of an existing microbiology method. This is especially true if the existing method is incorporated in a previously approved regulatory dossier, such as a New Drug Application (NDA) or Marketing Authorisation. (more…)

Tagged with: Michael J. Miller, Microbiology Consultants LLC, New Drug Application (NDA), PAT, Rapid microbiological methods (RMMs)

High-throughput PCR based diagnostics: Linking sample handling to molecular oncology risk groups

Issue 3 2010 / 24 June 2010 / Ehsan G. Karimiani, Stephan Mohr & Philip J. R. Day, University of Manchester

Cancer molecular pathology broadly relies on the comparison between diseased and normal tissues, with statistically validated differences revealing cancerassociated pathways. This approach, although comparatively one-dimensional, has been remarkably successful, enabling identification of many types of malignant biomarkers and providing the means to develop pharmaceutical agents directed against pertinent biological targets. Most typically during the progression of malignancies, pathologists employ morphological screening of cancerous tissues. However, this form of monitoring has significant limitations, particularly in the early stages of pre-treatment or during the clinical remission. (more…)

Tagged with: Cancer Biology, Ehsan G. Karimiani, PCR, Philip J. R. Day, qPCR, Stephan Mohr, University of Manchester

Biomarkers in the development of novel medicines for the treatment of cancer

Issue 3 2010 / 24 June 2010 / Hans Winkler, Global Head Oncology & Biomarker Programs, Ortho Biotech Oncology Research & Development, Johnson & Johnson

The pharmaceutical industry has reached a critical phase in its evolution. The cost and time to develop novel medicines has become unsustainable3. Reasons for this may include a much higher demand on evidence of safety and efficacy, rapidly increasing costs of contract research and the tremendous pressure on pricing and reimbursement from regulators and payers expecting higher benefit rates than the current average for newly launched products. Concomitant with these pressures we observe an ever decreasing R&D productivity which acerbates the problem2.

In this context, it is important to remind ourselves of the task to be achieved. First, a suitable target has to be identified whose inhibition will result in major effects on tumour growth and survival. (more…)

Tagged with: Biomarkers, Cancer Biology, Hans Winkler, Johnson & Johnson, Pharmacodynamic (PD), Pharmacokinetic (PK)

RNAi-based therapies for the treatment of HIV

Issue 3 2010 / 24 June 2010 / Marc S. Weinberg and Fiona van den Berg, Antiviral Gene Therapy Research Unit, Department of Molecular Medicine and Haematology, University of Witwatersrand

Since the discovery of RNA interference (RNAi) in 19981 and the demonstration of RNAi in mammalian cells in 20012, research into the mechanisms and applications of this pathway has moved swiftly. RNAi is capable of mediating potent and specific silencing of genes and has therefore shown promise in the development of alternative anti-viral therapies with the potential to avoid disadvantages associated with conventional drug regimens. A number of synthetic and expressed constructs have been investigated against HIV with varying success. Despite rapid progress, important hurdles need to be surmounted before a safe, effective and widely applicable therapy can be implemented clinically. Here, we review different RNAi-based strategies against HIV and highlight future developments necessary for the realisation of an effective anti-HIV therapy. (more…)

Tagged with: Fiona van den Berg, HAART (Highly-active Antiretroviral Therapy), HIV (Human Immunodeficiency Virus), Marc S. Weinberg, RNAi, siRNA Therapeutics, University of Witwatersrand

Trends in laboratory automation: From speed and simplicity to flexibility and information content

Issue 3 2010 / 24 June 2010 / Fernando A. Ramon Olayo, Manager, GlaxoSmithKline

The pharmaceutical industry has significantly influenced laboratory automation trends in the past two decades. The need to screen large collections of chemical entities in a short time with minimised consumption of reagents has driven a strong demand of parallelisation, automation, simplification and miniaturisation solutions from the suppliers of instruments, labware and assay technologies. Currently, the levels of automation and miniaturisation seem to have reached a plateau and the new paradigms are flexibility and information content. (more…)

Tagged with: Fernando A. Ramon Olayo, GlaxoSmithKline, HTS (High Throughput Screening), Lab Automation, microtitre plate

Cellular senescence as an anti-tumour mechanism

Issue 3 2010 / 24 June 2010 / Amancio Carnero, Scientist, Seville Biomedical Research Institute (IBIS/HUVR), Spanish National Research Council

One of the critical steps in human carcinogenesis is cellular immortalisation, a process in which cells must escape senescence and acquire an infinite lifespan. In the absence of immortalisation, although a cell might undergo malignant transformation, it could not proliferate indefinitely. Furthermore, it has been clearly established in vitro and in vivo that cellular senescence is a tumour suppressor mechanism induced by oncogenic stress1. Normal somatic cells grown in culture cease to proliferate, senesce, after a finite number of divisions.

This phenomenon, first described by Hayflick in 19652, is referred to as replicative senescence3. Senescent cells generally have a large, flattened morphology (see Figure 1). (more…)

Tagged with: Amancio Carnero, Cancer Biology, Cellular Pathways, senescence, Seville Biomedical Research Institute, Spanish National Research Council

Examining receptor activation: New technologies reveal how G protein-coupled receptors recognise ligands and talk to intracellular partners

Issue 3 2010 / 24 June 2010 / Thomas P. Sakmar, Laboratory of Molecular Biology & Biochemistry, Rockefeller University

Heptahelical G protein-coupled receptors (GPCRs) are arguably the most important single class of pharmaceutical drug targets in the human genome. According to Overington, of the 266 human targets for approved drugs, a remarkable 27 per cent correspond to rhodopsin-like, or Family A, GPCRs. Despite recent dramatic advances in targeting of kinases, the continued success of monoclonal antibody-based therapeutics and the advent of new drug entities like siRNAs, GPCRs remain the pre-eminent class of drug targets. (more…)

Tagged with: GPCRs, protein structure, Rockefeller University, Thomas P. Sakmar