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      Guidelines for the welfare and use of animals in cancer research

      other
      1 , * , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 18 , 10 , 11 , 12 ,   13 , 14 , 15 , 16 , 1 , * , An ad hoc committee of the National Cancer Research Institute 19
      British Journal of Cancer
      Nature Publishing Group
      animal welfare, cancer research, fundamental and translational research, replacement, reduction and refinement (3Rs), pilot studies, tumour models, genetically engineered mouse models, human tumour xenografts, orthotopic models, metastatic models, therapy, imaging, pharmocokinetic, pharmacodynamic and efficacy studies, drugs, radiation therapy, imaging techniques, anaesthesia, restraint, humane endpoints, tumour burden, clinical signs, publication, best practice

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          Abstract

          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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          Most cited references166

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          Cancer genes and the pathways they control.

          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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            Targeted cancer therapy.

            Disruption of the normal regulation of cell-cycle progression and division lies at the heart of the events leading to cancer. Complex networks of regulatory factors, the tumour microenvironment and stress signals, such as those resulting from damaged DNA, dictate whether cancer cells proliferate or die. Recent progress in understanding the molecular changes that underlie cancer development offer the prospect of specifically targeting malfunctioning molecules and pathways to achieve more effective and rational cancer therapy.
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              Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.

              Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of KrasG12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, KrasG12D expression and Ink4a/Arf deficiency resulted in an earlier appearance of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of these tumors bears striking resemblance to the human disease, possessing a proliferative stromal component and ductal lesions with a propensity to advance to a poorly differentiated state. These findings in the mouse provide experimental support for the widely accepted model of human pancreatic adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the INK4A/ARF tumor suppressors function to constrain the malignant conversion of these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                25 May 2010
                25 May 2010
                25 May 2010
                : 102
                : 11
                : 1555-1577
                Affiliations
                [1 ]simpleCancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research , Cotswold Road, Sutton, Surrey SM2 5NG, UK
                [2 ]simpleComprehensive Cancer Imaging Centre, Imperial College London Faculty of Medicine, Hammersmith Hospital Campus , Du Cane Road, London W12 ONN, UK
                [3 ]simpleCentre for Cancer & Inflammation, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square , London EC1M 6BQ, UK
                [4 ]simpleHelen Diller Family Comprehensive Cancer Center, University of California San Francisco 1450 3rd Street , San Francisco, CA 94158, USA
                [5 ]simplePaterson Institute for Cancer Research, University of Manchester , Wilmslow Road, Manchester M20 4BX, UK
                [6 ]simpleOXiGENE Inc., 701 Gateway Boulevard , San Francisco, CA 94080, USA
                [7 ]simpleUniversity of Bradford , Richmond Road, Bradford BD7 1DP, UK
                [8 ]simpleGlaxoSmithkline Pharmaceutical R&D, PO Box 13398, Five Moore Drive, N2.2210.2B , Research Triangle Park, NC 27709-3398, USA
                [9 ]simpleCancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms , Herts EN6 3LD, UK
                [10 ]simpleTenovus Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital , Southampton SO16 6YD, UK
                [11 ]simpleCancer Research Technology Development Laboratories, Wolfson Institute for Biomedical Research, University College London , Gower Street, London WC1E 6BT, UK
                [12 ]simpleNational Centre for the Replacement, Refinement and Reduction of Animals in Research 20, Park Crescent , London W1B 1AL, UK
                [13 ]simpleSchool of Pharmacy and Pharmaceutical Sciences, University of Manchester, Stopford Building , Oxford Road, Manchester M13 9PT, UK
                [14 ]simpleDepartment of Oncology, K Floor, School of Medicine, University of Sheffield , Beech Hill Road, Sheffield S10 2RX, UK
                [15 ]simpleDivision of Pre-Clinical Oncology & PRECOS, D Floor West Block, Queen's Medical Centre, University Hospital , Nottingham NG7 2UH, UK
                [16 ]simpleCancer Bioscience, AstraZeneca, Mereside, Alderley Park, Macclesfield , Cheshire SK10 4TG, UK
                [17 ]simpleThe Home Office, ASPD (mail point 1B), 1st floor Seacole Building , 2 Marsham Street, London W1P 4DF, UK
                [18 ]Current address: simpleMedical Research Council, 20 Park Crescent London W1B 1AL, UK
                Author notes
                [19]

                The National Cancer Research Institute (NCRI) is a partnership of 21 organisations from the government, charity and commercial sectors who support cancer research in the UK. Further information about NCRI can be found at http://www.ncri.org.uk

                [*]

                Observers: V Navaratnam and S Ryder 17

                Article
                6605642
                10.1038/sj.bjc.6605642
                2883160
                20502460
                c199f88f-e311-4030-aaf2-8e576c7c8dcd
                Copyright © 2010 Cancer Research UK

                This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 05 March 2010
                : 15 March 2010
                Categories
                Guidelines

                Oncology & Radiotherapy
                human tumour xenografts,radiation therapy,tumour models,genetically engineered mouse models,drugs,imaging techniques,publication,therapy,imaging,animal welfare,pilot studies,humane endpoints,replacement, reduction and refinement (3rs),tumour burden,cancer research,metastatic models,anaesthesia,orthotopic models,restraint,clinical signs,best practice,pharmocokinetic, pharmacodynamic and efficacy studies,fundamental and translational research

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