Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

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Guidelines for the welfare and use of animals in cancer research

Administration of substances to laboratory animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. For all species, many different routes are available for administration of substances. The research team and IACUC members should be aware of reasons for selecting specific routes and of training and competency necessary for personnel to use these routes effectively. Once a route is selected, issues such as volume of administration, site of delivery, pH of the substance, and other factors must be considered to refine the technique. Inadequate training or inattention to detail during this aspect of a study may result in unintentional adverse effects on experimental animals and confounded results.

Administration of substances to laboratory animals: routes of administration and factors to consider.

Chronic, low-level elevation of circulating interleukin (IL)-6 is observed in disease states as well as in many outwardly healthy elderly individuals. Increased plasma IL-6 is also observed after intense, prolonged exercise. In the context of skeletal muscle, IL-6 has variously been reported to regulate carbohydrate and lipid metabolism, increase satellite cell proliferation, or cause muscle wasting. In the present study, we used a rodent local infusion model to deliver modest levels of IL-6, comparable to that present after exercise or with chronic low-level inflammation in the elderly, directly into a single target muscle in vivo. The aim of this study was to examine the direct effects of IL-6 on skeletal muscle in the absence of systemic changes in this cytokine. Data included cellular and molecular markers of cytokine and growth factor signaling (phosphorylation and mRNA content) as well as measurements to detect muscle atrophy. IL-6 infusion resulted in muscle atrophy characterized by a preferential loss of myofibrillar protein (-17%). IL-6 induced a decrease in the phosphorylation of ribosomal S6 kinase (-60%) and STAT5 (-33%), whereas that of STAT3 was increased approximately twofold. The changes seen in the IL-6-infused muscles suggest alterations in the balance of growth factor-related signaling in favor of a more catabolic profile. This suggests that downregulation of growth factor-mediated intracellular signaling may be a mechanism contributing to the development of muscle atrophy induced by elevated IL-6.

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IL-6-induced skeletal muscle atrophy.

Drug delivery to the central nervous system by polymeric nanoparticles: what do we know?

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Biological evaluation of medical devices

This article is the result of an initiative between the European Federation of Pharmaceutical Industries Associations (EFPIA) and the European Centre for the Validation of Alternative Methods (ECVAM). Its objectives are to provide the researcher in the safety evaluation laboratory with an up-to-date, easy-to-use set of data sheets to aid in the study design process whilst at the same time affording maximum welfare considerations to the experimental animals. Although this article is targeted at researchers in the European Pharmaceutical Industry, it is considered that the principles underpinning the data sets and refinement proposals are equally applicable to all those who use these techniques on animals in their research, whether in research institutes, universities or other sectors of industry. The implications of this article may lead to discussion with regulators, such as those responsible for pharmacopoeial testing. There are numerous publications dealing with the administration of test substances and the removal of blood samples, and many laboratories also have their own "in-house" guidelines that have been developed by custom and practice over many years. Within European Union Directive 86/609EEC1 we have an obligation to refine experiments to cause the minimum amount of stress. We hope that this article will provide background data useful to those responsible for protocol design and review. This guide is based on peer-reviewed publications whenever possible, but where this is not possible we have used "in-house" data and the experience of those on the working party (as well as helpful comments submitted by the industry) for a final opinion. The guide also addresses the continuing need to refine the techniques associated with the administration of substances and the withdrawal of blood, and suggests ways of doing so. Data-sharing between laboratories should be encouraged to avoid duplication of animal work, as well as sharing practical skills concerning animal welfare and scientific problems caused by "overdosing" in some way or another. The recommendations in this guide refer to the "normal" animal, and special consideration is needed, for instance, during pregnancy and lactation. Interpretation of studies may be confounded when large volumes are administered or excessive sampling employed, particularly if anaesthetics are used.

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Jean-Marc Vidal

Papers

A good practice guide to the administration of substances and removal of blood, including routes and volumes