The role of mouse tumour models in the discovery and development of anticancer drugs.

Our understanding of cancer biology has increased substantially over the past 30 years. Despite this, and an increasing pharmaceutical company expenditure on research and development, the approval of novel oncology drugs during the past decade continues to be modest. In addition, the attrition of agents during clinical development remains high. This attrition can be attributed, at least in part, to the clinical development being underpinned by the demonstration of predictable efficacy in experimental models of human tumours. This review will focus on the range of models available for the discovery and development of anticancer drugs, from traditional subcutaneous injection of tumour cell lines to mice genetically engineered to spontaneously give rise to tumours. It will consider the best time to use the models, along with practical applications and shortcomings. Finally, and most importantly, it will describe how these models reflect the underlying cancer biology and how well they predict efficacy in the clinic. Developing a line of sight to the clinic early in a drug discovery project provides clear benefit, as it helps to guide the selection of appropriate preclinical models and facilitates the investigation of relevant biomarkers.

New and emerging immune-targeted drugs for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component that constitutes the most common progressive and disabling neurological condition in young adults. Injectable immunomodulatory medicines such as interferon drugs and glatiramer acetate have dominated the MS market for over the past two decades but this situation is set to change. This is because of: (i) patent expirations, (ii) the introduction of natalizumab, which targets the interaction between leukocytes and the blood-CNS barrier, (iii) the launch of three oral immunomodulatory drugs (fingolimod, dimethyl fumarate and teriflunomide), with another (laquinimod) under regulatory review and (iv) a number of immunomodulatory monoclonal antibodies (alemtuzumab, daclizumab and ocrelizumab) about to enter the market. Current and emerging medicines are reviewed and their impact on people with MS considered.

Multiple sclerosis and the blood-central nervous system barrier.

The central nervous system (CNS) is isolated from the blood system by a physical barrier that contains efflux transporters and catabolic enzymes. This blood-CNS barrier (BCNSB) plays a pivotal role in the pathophysiology of multiple sclerosis (MS). It binds and anchors activated leukocytes to permit their movement across the BCNSB and into the CNS. Once there, these immune cells target particular self-epitopes and initiate a cascade of neuroinflammation, which leads to the breakdown of the BCNSB and the formation of perivascular plaques, one of the hallmarks of MS. Immunomodulatory drugs for MS are either biologics or small molecules, with only the latter having the capacity to cross the BCNSB and thus have a propensity to cause CNS side effects. However, BCNSB penetration is a desirable feature of MS drugs that have molecular targets within the CNS. These are nabiximols and dalfampridine, which target cannabinoid receptors and potassium channels, respectively. Vascular cell adhesion molecule-1, present on endothelial cells of the BCNSB, also serves as a drug discovery target since it interacts with α4-ß1-integrin on leucocytes. The MS drug natalizumab, a humanized monoclonal antibody against α4-ß1-integrin, blocks this interaction and thus reduces the movement of immune cells into the CNS. This paper further elaborates on the role of the BCNSB in the pathophysiology and pharmacotherapy of MS.

Overview of experimental models of the blood-brain barrier in CNS drug discovery.

The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic enzymes. To cross the BBB, a drug must possess the appropriate physicochemical properties to achieve a sufficient time-concentration profile in brain interstitial fluid (ISF). In this overview, we review techniques to measure BBB permeation, which is evidenced by the free concentration of compound in brain ISF over time. We consider a number of measurement techniques, including in vivo microdialysis and brain receptor occupancy following perfusion. Consideration is also given to the endothelial and nonendothelial cell systems used to assess both the BBB permeation of a test compound and its interactions with egress transporters, and computer models employed for predicting passive permeation and the probability of interactions with BBB transporters.

Translational CNS medicines research.

The major imperative of the pharmaceutical industry is to effectively translate insights gained from basic research into new medicines. This task is toughest for CNS disorders. Compared with non-CNS drugs, CNS drugs take longer to get to market and their attrition rate is greater. This is principally because of the complexity of the human brain (the cause of many brain disorders remains unknown), the liability of CNS drugs to cause CNS side effects (which limits their use) and the requirement of CNS medicines to cross the blood-CNS barrier (BCNSB) (which restricts their ability to interact with their CNS target). In this review we consider the factors that are important in translating neuroscience research into CNS medicines.

The role of the blood brain barrier in neurodegenerative disorders and their treatment.

Neurodegenerative disorders represent a major medical challenge that is set to increase substantially in the decades ahead with the massive increase in the number of people in the world aged 65 or more. Neuroprotective therapeutics have the potential to play a key role in helping manage this growing global burden of long-term neurological care. However, neuropharmaceutical research is associated with significant challenges including: (1) the complexity of the brain (the cause of the majority of neurodegenerative disorders remains unknown); (2) the liability of central nervous system (CNS) drugs to cause CNS side effects (which limits their use); and (3) the requirement of neuropharmaceuticals to cross the blood-brain barrier (BBB). The BBB itself also plays a key role in most (if not all) neurodegenerative disorders since BBB dysfunction inevitably leads to inflammatory change including the movement of immune cells and immune mediators into the brain, which then contribute to the process of neurodegeneration. This review focuses on the role of the BBB in both neurodegenerative disorders and neuropharmaceutical research.

Neuroprotective therapeutics for Alzheimer's disease: progress and prospects.

The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future.

Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis.

Teriflunomide, being developed as a potential oral treatment for multiple sclerosis (MS) by sanofi-aventis, is the active metabolite of the rheumatoid arthritis drug leflunomide. Both teriflunomide and leflunomide are inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase, which is critically involved in pyrimidine synthesis. The production of activated T-cells largely depends on de novo pyrimidine synthesis, and thus pyrimidine depletion is thought to result in the inhibition of immune cell proliferation. Therapeutic efficacy of teriflunomide has been demonstrated in vivo in an experimental autoimmune encephalomyelitis model of MS using Dark Agouti rats. In a phase II, randomized, double-blind, placebo-controlled clinical trial of patients with relapsing-remitting MS, treatment with teriflunomide reduced the number of active lesions in the brain and preliminary evidence indicated a slowing in the development of disability. Recently reported data from the phase III TEMSO clinical trial support these initial findings. Compared with current therapies, teriflunomide has the advantage of oral administration. Thus, if good efficacy is demonstrated, teriflunomide may have a role to play in the future treatment of MS.

Neurochemical changes in a double transgenic mouse model of Alzheimer's disease fed a pro-oxidant diet.

Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months. The neocortex, cerebellum, hippocampus and striatum were assayed for their monoamine and monoamine metabolite content using HPLC with electrochemical detection. Striatal tyrosine hydroxylase (TOH) levels were analysed by Western blotting. In the striatum, female TASTPM mice had higher levels of DOPAC and male TASTPM mice had higher levels of 5-HIAA compared to wildtype mice. Administration of pro-oxidant diet increased striatal MHPG, turnover of NA and 5-HT levels in female TASTPM mice compared to TASTPM mice fed control diet. The pro-oxidant diet also decreased DOPAC levels in female TASTPM mice compared to those fed control diet. Striatal TOH did not depend on diet, gender or genotype. In the neocortex, the TASTPM genotype increased levels of 5-HIAA in male mice fed control diet compared to wildtype mice. In the cerebellum, the TASTPM genotype led to decreased levels of HVA (male mice only) and also decreased turnover of DA (female mice only) compared to wildtype mice. These data suggest a sparing of monoaminergic neurones in the cortex, striatum and hippocampus of TASTPM mice fed pro-oxidant diet and could be indicative of increased activity in corticostriatal circuits. The decreased cerebellar levels of HVA and turnover of DA in TASTPM mice hint at possible axonal degeneration within this subregion.

Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds.

The need to discover and develop safe and effective new medicines is greatest for disorders of the CNS. A core requirement for an effective neurotherapeutic agent is an ability to cross the blood-brain barrier and remain in the brain interstitial fluid (ISF) for a sufficient duration and concentration to evoke the desired therapeutic effect. Measuring the free concentration of a neuroactive compound in brain ISF is therefore an essential step in the critical path towards the development of a CNS medicine. In vivo microdialysis provides a powerful method for the measurement of endogenous and exogenous substances in the ISF surrounding the probe and so it represents an important tool in CNS drug discovery. It can also be used to measure the pharmacodynamic response of neuroactive compounds by measuring neurotransmitters and second messengers. Another approach to measure both pharmacokinetics and the pharmacodynamics of neuroactive compounds is the measurement of receptor occupancy, which has the advantage of being applicable to the study of humans as well as experimental animals. Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds clearly improve understanding of the efficacy and safety of drug candidates, which improves both the efficiency and the effectiveness of CNS medicines research.

The role of the blood-CNS barrier in CNS disorders and their treatment.

The physical barrier between blood and the CNS (the blood-brain barrier, the blood-spinal cord barrier and the blood-CSF barrier) protects the CNS from both toxic and pathogenic agents in the blood. It is now clear that disruption of the blood-CNS barrier plays a key role in a number of CNS disorders, particularly those associated with neurodegeneration. Such disruption is inevitably accompanied by inflammatory change, as immune cells and immune mediators gain access to the brain or spinal cord. The blood-CNS barrier also presents a major obstacle for potential CNS medicines. Robust methods to assess CNS permeation are therefore essential for CNS drug discovery, particularly when brain pharmacokinetics are taken into account and especially when such measures are linked to neurochemical, physiological, behavioural or neuroimaging readouts of drug action. Drug candidates can be successfully designed to cross the blood-CNS barrier, but for those that can't there is the possibility of entry with a delivery system that facilitates the movement of drug candidate across the blood-CNS barrier.

Pharmacotherapy for multiple sclerosis: progress and prospects.

Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component, and constitutes the most common progressive and disabling neurological condition in young adults. Currently available therapies predominantly include biological agents (beta-interferon and a mAb to a cell adhesion molecule [integrin] on lymphocytes that is involved in the adhesion of lymphocytes to the blood-brain barrier) that attenuate the neuroinflammatory response; however, the ability of these agents to modify the disease course of MS is only modest at best. Because of the inadequacy of current treatment options, there is a need for the development of more effective disease-modifying therapies (eg, sodium channel blockers), along with new drugs to treat specific symptoms of MS, such as fatigue.

Neurodegenerative disorders and their treatment.

This Society for Medicines Research symposium was held on June 6, 2007, at the Eli Lilly Research Centre in Windlesham, Surrey, United Kingdom. The meeting, organized by Eric Karran and Alan Palmer, reviewed the progress made, and the challenges still to be overcome, in discovering safe and effective therapies for the most common chronic neurodegenerative diseases: Alzheimer's disease, Parkinson's disease and multiple sclerosis. Progress in establishing effective pharmacotherapy for acute neurodegenerative disorders (stroke and traumatic brain injury) was also reviewed.

Society for Medicines Research: 40th anniversary symposium.

The recent symposium of the Society for Medicines Research (SMR), held on December 11, 2006, in Westminster, UK, celebrated the 40th anniversary of the formation of the SMR. The meeting began with an overview of future strategies for medicines research and its funding in Europe. This session was followed by the 2006 SMR Award lecture, which was given by Dr. Napoleone Ferrara of Genentech, for the development of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab for the treatment of cancer. The remainder of the meeting showcased the best of medicines research in the United Kingdom by highlighting a number of drug discovery success stories from several UK biotech companies, which covered the therapeutic areas of central nervous system, cancer and viral infection, along with regenerative medicine.

CNS drug discovery: challenges and solutions.

The worldwide market for therapies for central nervous system (CNS) disorders was valued at around US dollars 50 billion in 2001, and is set to grow sharply in the years ahead. This is because of a marked increase in the number of people aged over 65 (the "baby boomer" effect), which will lead to increased demand for more safe and effective medicines for CNS disorders. This one-day Society for Medicines Research symposium, held September 23, 2004, in London, United Kingdom, was organized by Dr. Alan M. Palmer (Pharmidex, London, U.K.) and Prof. F. Anne Stephenson (School of Pharmacy, University of London, U.K.). More than 100 delegates heard a scholarly and comprehensive review of the challenges currently facing CNS research and development, which was accompanied by consideration of a variety of innovative solution strategies. The meeting considered: 1) how to identify and validate targets for potential CNS drugs; 2) how to assess brain penetration (both in vitro and in vivo); 3) how to develop in silico methodologies to predict blood-brain barrier penetration; 4) how to assess therapeutic efficacy (both in vitro and in vivo); 5) how to establish reliable biomarkers to guide decision making; and 6) how to effectively apply magnetic resonance imaging to CNS drug discovery.

Therapeutic strategies for tissue regeneration.

Tissue regeneration represents an emerging approach to the development of new medicines. It has even been described as the major therapeutic approach of the 21st century. Realization of this promise depends on overcoming a number of significant challenges. In the Society for Medicines Research symposium, held on June 6, 2005, in London, United Kingdom, and organized by Prof. Ian Morris (Hull York Medical School, York, UK) and Dr. Alan M. Palmer (Pharmidex, London, UK), several visionaries shared their confidence and determination to overcome these challenges. It is clear that persistence in this difficult area of research is increasingly paying dividends as the commercial potential of strategies for tissue regeneration are recognized by the biopharmaceutical industry, investors and government funding agencies worldwide.