Pre-clinical research in small animals using radiotherapy technology--a bidirectional translational approach.

For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

[1]  María-Ester Brandan,et al.  Use of an orthovoltage X-ray treatment unit as a radiation research system in a small-animal cancer model , 2008, Journal of experimental & clinical cancer research : CR.

[2]  S Mutic,et al.  MicroRT-small animal conformal irradiator. , 2007, Medical physics.

[3]  A. Martinez,et al.  Effects of continuous low-dose-rate brachytherapy on the rectum of the rat. , 1996, Radiation research.

[4]  John Wong,et al.  Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. , 2013, International journal of radiation oncology, biology, physics.

[5]  E. B. Moore,et al.  A cesium-137 irradiator for small laboratory animals. , 1973, Radiology.

[6]  Erik Tryggestad,et al.  Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts. , 2012, Translational oncology.

[7]  Peter Kazanzides,et al.  Image-guided small animal radiation research platform: calibration of treatment beam alignment , 2009, Physics in medicine and biology.

[8]  Rod J. Rohrich,et al.  An athymic rat model of cutaneous radiation injury designed to study human tissue-based wound therapy , 2012, Radiation oncology.

[9]  G. Hartmann,et al.  A system for stereotactic irradiation and magnetic resonance evaluations in the rat brain. , 1995, International journal of radiation oncology, biology, physics.

[10]  T D Solberg,et al.  Dosimetric characterization of an image-guided stereotactic small animal irradiator , 2011, Physics in medicine and biology.

[11]  N. Kouyama,et al.  The effect of gamma knife irradiation on functions of striatum in rats. , 2005, Journal of neurosurgery.

[12]  Johannes A Langendijk,et al.  The impact of heart irradiation on dose-volume effects in the rat lung. , 2007, International journal of radiation oncology, biology, physics.

[13]  Iulian Iordachita,et al.  Accuracy of Off-Line Bioluminescence Imaging to Localize Targets in Preclinical Radiation Research. , 2013, Radiation research.

[14]  J. Thomas,et al.  Human tumour xenografts established and serially transplanted in mice immunologically deprived by thymectomy, cytosine arabinoside and whole-body irradiation. , 1980, British Journal of Cancer.

[15]  I. Zuna,et al.  Improved therapeutic response by distinct timing of multiple heat treatments during interstitial radiation in the Dunning R3327 prostate tumor model , 1998, Journal of Cancer Research and Clinical Oncology.

[16]  W. Vandertop,et al.  Experimental iodine-125 seed irradiation of intracerebral brain tumors in nude mice , 2007, Radiation oncology.

[17]  Jean-Philippe Pignol,et al.  Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation , 2012, Breast Cancer Research and Treatment.

[18]  Erik Tryggestad,et al.  Small animal radiotherapy research platforms , 2011, Physics in medicine and biology.

[19]  C. Limoli,et al.  Stem Cell Transplantation Strategies for the Restoration of Cognitive Dysfunction Caused by Cranial Radiotherapy , 2011, Journal of visualized experiments : JoVE.

[20]  R. Hill,et al.  Mitigation of Lung Injury after Accidental Exposure to Radiation , 2011, Radiation research.

[21]  Hongjun Song,et al.  Localized CT-Guided Irradiation Inhibits Neurogenesis in Specific Regions of the Adult Mouse Brain , 2011, Radiation research.

[22]  R. Bristow,et al.  Biodosimetry using radiation-induced micronuclei in skin fibroblasts , 2011, International journal of radiation biology.

[23]  Peter Kazanzides,et al.  High-resolution, small animal radiation research platform with x-ray tomographic guidance capabilities. , 2008, International journal of radiation oncology, biology, physics.

[24]  J. Wondergem,et al.  The influence of misonidazole on the radiation response of murine tumors of different size: possible artifacts caused by pentobarbital sodium anesthesia. , 1981, International journal of radiation oncology, biology, physics.

[25]  J. Régis,et al.  [Experimental radiosurgery in rats using gamma a "gamma knife". Description of a stereotactic device for small laboratory animals]. , 1996, Neuro-Chirurgie.

[26]  W. Dörr Radiobiological models of normal tissue reactions. , 1998, Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al].

[27]  R. Mirimanoff,et al.  Combined radioimmunotherapy and radiotherapy of human colon carcinoma grafted in nude mice. , 1995, Cancer research.

[28]  D. Chmelevsky,et al.  Kinetics of recovery from sublethal radiation damage in four murine tumors. , 1990, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[29]  Andries G Visser,et al.  Dose-volume effects in rat thoracolumbar spinal cord: the effects of nonuniform dose distribution. , 2007, International journal of radiation oncology, biology, physics.

[30]  Gabriel Charest,et al.  Applications of Gamma Knife Radiosurgery for Experimental Investigations in Small Animal Models , 2011 .

[31]  J. Carmichael,et al.  Human tumour xenografts growing in immunodeficient mice: a useful model for assessing chemotherapeutic agents in bronchial carcinoma. , 1986, Thorax.

[32]  P. Levendag,et al.  Dose-effect relation of interstitial low-dose-rate radiation (Ir192) in an animal tumor model. , 1990, International journal of radiation oncology, biology, physics.

[33]  Erik Tryggestad,et al.  Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides , 2010, Nature Medicine.

[34]  M. Baumann,et al.  Response of human squamous cell carcinoma xenografts of different sizes to irradiation: relationship of clonogenic cells, cellular radiation sensitivity in vivo, and tumor rescuing units. , 1990, Radiation research.

[35]  F. Verhaegen,et al.  Relative biologic effectiveness in terms of tumor response of 125I implants compared with 60Co gamma rays. , 2005, International journal of radiation oncology, biology, physics.

[36]  A. Franko,et al.  Irradiation of mouse lungs causes a dose-dependent increase in lung weight. , 1982, International journal of radiation oncology, biology, physics.

[37]  K. Sheng,et al.  A rabbit irradiation platform for outcome assessment of lung stereotactic radiosurgery. , 2009, International journal of radiation oncology, biology, physics.

[38]  R. Nath,et al.  Development of a shielded 241Am applicator for continuous low dose rate irradiation of rat rectum. , 1992, International journal of radiation oncology, biology, physics.

[39]  A Novel Stereotactic Device for Spinal Irradiation in Rats Designed for a Linear Accelerator , 2010, Stereotactic and Functional Neurosurgery.

[40]  A. Taghian,et al.  The effect of the overall treatment time of fractionated irradiation on the tumor control probability of a human soft tissue sarcoma xenograft in nude mice. , 1995, International journal of radiation oncology, biology, physics.

[41]  Richard Hill,et al.  A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics , 2013, Journal of visualized experiments : JoVE.

[42]  Continuous, pulsed or single acute irradiation of a transplanted rodent tumour model. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[43]  T H Farncombe Software-based respiratory gating for small animal conebeam CT. , 2008, Medical physics.

[44]  T R Mackie,et al.  History of tomotherapy , 2006, Physics in medicine and biology.

[45]  Timothy D Solberg,et al.  An Orthotopic Lung Tumor Model for Image-Guided Microirradiation in Rats , 2010, Radiation research.

[46]  R. Foà,et al.  Xenotransplantation in immunosuppressed nude mice of human solid tumors and acute leukemias directly from patients orin vitro cell lines , 1989, La Ricerca in clinica e in laboratorio.

[47]  H. Zischka,et al.  Radiation–Induced Signaling Results in Mitochondrial Impairment in Mouse Heart at 4 Weeks after Exposure to X-Rays , 2011, PloS one.

[48]  P. Gutin,et al.  Long-Term Impact of Radiation on the Stem Cell and Oligodendrocyte Precursors in the Brain , 2007, PloS one.

[49]  Frank Verhaegen,et al.  Development and validation of a treatment planning system for small animal radiotherapy: SmART-Plan. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[50]  R. Gonzalez,et al.  MRI Changes in the Rat Hippocampus following Proton Radiosurgery , 2004, Stereotactic and Functional Neurosurgery.

[51]  Bernhard Kimmig,et al.  HDR brachytherapy irradiation of the jaw - as a new experimental model of radiogenic bone damage. , 2008, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[52]  Gabriel Charest,et al.  Polymer gel in rat skull to assess the accuracy of a new rat stereotactic device for use with the Gamma Knife , 2009, Acta Neurochirurgica.

[53]  I. Iordachita,et al.  CT Guidance is Needed to Achieve Reproducible Positioning of the Mouse Head for Repeat Precision Cranial Irradiation , 2010, Radiation research.

[54]  Erik Tryggestad,et al.  Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease , 2008, Neurobiology of Disease.

[55]  J. Battista,et al.  Computed tomographic assessment of radiation induced damage in the lung of normal and WR 2721 protected LAF1 mice. , 1986, International journal of radiation oncology, biology, physics.

[56]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[57]  R. Timmerman,et al.  Pulmonary Hilar Stereotactic Body Radiation Therapy in the Rat , 2007, Technology in cancer research & treatment.

[58]  Eugene Wong,et al.  Implementation and commissioning of an integrated micro-CT∕RT system with computerized independent jaw collimation. , 2013, Medical physics.

[59]  Salomeh Jelveh,et al.  Effects of lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation. , 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[60]  R Nath,et al.  Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64. , 1999, Medical physics.

[61]  F. Stewart,et al.  Late radiation damage in the mouse bladder as measured by increased urination frequency. , 1978, Radiation research.

[62]  T. Unno,et al.  Reduction of food intake following X-ray irradiation of rats—involvement of visceral afferent nerves , 2002, Autonomic Neuroscience.

[63]  D. Kondziolka,et al.  Dosimetric comparison of the Leksell Gamma Knife Perfexion and 4C. , 2008, Journal of neurosurgery.

[64]  Sasa Mutic,et al.  Progress toward a microradiation therapy small animal conformal irradiator. , 2006, Medical physics.

[65]  M. Goodman Gamma knife radiosurgery: current status and review. , 1990, Southern medical journal (Birmingham, Ala. Print).

[66]  M. Wannenmacher,et al.  Dose-dependent differential effects of low and pulsed dose-rate brachytherapy in a radioresistant syngenic rat prostate tumour model , 2002, International journal of radiation biology.

[67]  P. van Luijk,et al.  Techniques for precision irradiation of the lateral half of the rat cervical spinal cord using 150 MeV protons [corrected]. , 2001, Physics in medicine and biology.

[68]  S. Belinsky,et al.  Refinement of an Orthotopic Lung Cancer Model in the Nude Rat , 2001, Veterinary pathology.

[69]  W. Enghardt,et al.  Tumour bed irradiation of human tumour xenografts in a nude rat model using a common X-ray tube , 2010, Journal of Biosciences.

[70]  D. Zips,et al.  Experimentelle Tumortherapie , 2012, Strahlentherapie und Onkologie.

[71]  T. K. Yeung,et al.  Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. , 1988, The British journal of radiology.

[72]  J. Debus,et al.  Relative biological effectiveness of carbon ions for local tumor control of a radioresistant prostate carcinoma in the rat. , 2011, International journal of radiation oncology, biology, physics.

[73]  W. Dörr,et al.  Early changes in mouse urinary bladder function following fractionated X irradiation. , 1992, Radiation research.

[74]  F. Frassica,et al.  Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells , 2011, Proceedings of the National Academy of Sciences.

[75]  A. J. van der Kogel,et al.  High dose rate (HDR) and low dose rate (LDR) interstitial irradiation (IRT) of the rat spinal cord. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[76]  Calibration of an x-ray cabinet unit for radiobiology use. , 2006, Physics in medicine and biology.

[77]  D A Jaffray,et al.  Characterization of image quality and image-guidance performance of a preclinical microirradiator. , 2011, Medical physics.

[78]  M. Bibby,et al.  Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. , 2004, European journal of cancer.

[79]  J. Kummermehr,et al.  Radiation response of the mouse tongue epithelium. , 1986, The British journal of cancer. Supplement.

[80]  J. Cadeddu,et al.  Efficacy of ablative high-dose-per-fraction radiation for implanted human renal cell cancer in a nude mouse model. , 2006, European urology.

[81]  Paul Keall,et al.  Commissioning of a novel microCT/RT system for small animal conformal radiotherapy , 2009, Physics in medicine and biology.

[82]  J. Williamson,et al.  Update of AAPM Task Group No. 43 Report: A revised AAPM protocol for brachytherapy dose calculations. , 2004 .

[83]  P. Okunieff,et al.  Investigations of antioxidant-mediated protection and mitigation of radiation-induced DNA damage and lipid peroxidation in murine skin , 2013, International journal of radiation biology.

[84]  Piotr Zygmanski,et al.  A multipurpose quality assurance phantom for the small animal radiation research platform (SARRP) , 2012, Physics in medicine and biology.

[85]  B. Paquette,et al.  Pre-irradiation of mouse mammary gland stimulates cancer cell migration and development of lung metastases , 2013, British Journal of Cancer.

[86]  M J Welch,et al.  Small animal imaging: current technology and perspectives for oncological imaging , 2002 .

[87]  Carl Virtanen,et al.  In Vivo Optical Imaging of Tumor and Microvascular Response to Ionizing Radiation , 2012, PloS one.

[88]  W. Dörr,et al.  Effect of selective inhibitors of inflammation on oral mucositis: preclinical studies. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[89]  I. Blümcke,et al.  Hypofractionated Stereotactic Radiotherapy to the Rat Hippocampus , 2007, Strahlentherapie und Onkologie.

[90]  Christopher H Contag,et al.  Design and evaluation of a variable aperture collimator for conformal radiotherapy of small animals using a microCT scanner. , 2007, Medical physics.

[91]  D. Jaffray,et al.  Depletion of New Neurons by Image Guided Irradiation , 2011, Frontiers in Neuroscience.

[92]  E. Rofstad,et al.  Tumour growth delay following single dose irradiation of human melanoma xenografts. Correlations with tumour growth parameters, vascular structure and cellular radiosensitivity. , 1985, British Journal of Cancer.

[93]  J. Overgaard,et al.  Reducing acute and chronic hypoxia in tumours by combining nicotinamide with carbogen breathing. , 1994, Acta oncologica.

[94]  W. Dörr,et al.  Accelerated repopulation of mouse tongue epithelium during fractionated irradiations or following single doses. , 1990, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[95]  M. Krause,et al.  Does heterogeneity of pimonidazole labelling correspond to the heterogeneity of radiation-response of FaDu human squamous cell carcinoma? , 2005, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[96]  Y. Kawakami,et al.  Gamma Knife Irradiation of Injured Sciatic Nerve Induces Histological and Behavioral Improvement in the Rat Neuropathic Pain Model , 2013, PloS one.

[97]  A. P. van den Berg,et al.  Tumor hypoxia--a confounding or exploitable factor in interstitial brachytherapy? Effects of tissue trauma in an experimental rat tumor model. , 2000, International journal of radiation oncology, biology, physics.

[98]  David A Jaffray,et al.  Two-dimensional inverse planning and delivery with a preclinical image guided microirradiator. , 2013, Medical physics.

[99]  Hyun-Tai Chung,et al.  Development of a stereotactic device for gamma knife irradiation of small animals. , 2008, Journal of Korean Neurosurgical Society.

[100]  Wolfhard Semmler,et al.  Intrinsic respiratory gating in small-animal CT , 2008, European Radiology.

[101]  R. Kotb,et al.  Efficacy of cisplatin and Lipoplatin™ in combined treatment with radiation of a colorectal tumor in nude mouse. , 2013, Anticancer research.

[102]  Kitti Brinyiczki,et al.  Development of a small-animal focal brain irradiation model to study radiation injury and radiation-injury modifiers , 2013, International journal of radiation biology.

[103]  Lennart Lindborg,et al.  RBE of low energy electrons and photons , 2010, Physics in medicine and biology.

[104]  J. Seuntjens,et al.  A new formalism for reference dosimetry of small and nonstandard fields. , 2008, Medical physics.

[105]  W. Dörr,et al.  Repopulation in mouse oral mucosa: changes in the effect of dose fractionation. , 2000, International journal of radiation biology.

[106]  G. Nikiforidis,et al.  In vivo small animal imaging: current status and future prospects. , 2010, Medical physics.

[107]  Douglas B. Evans,et al.  Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice , 2009, Nature Protocols.

[108]  J. Galvin,et al.  Radiochromic film dosimetry: recommendations of AAPM Radiation Therapy Committee Task Group 55. American Association of Physicists in Medicine. , 1998, Medical physics.

[109]  M. Krause,et al.  Heterogeneity of tumour response to combined radiotherapy and EGFR inhibitors: Differences between antibodies and TK inhibitors , 2009, International journal of radiation biology.

[110]  B. Lyons,et al.  Response of a brachytherapy model using 125I in a murine tumor system. , 1989, Radiation research.

[111]  F. Sarkar,et al.  Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model , 2007, BMC Cancer.

[112]  Jeffrey P. Lopez,et al.  A NOVEL PHANTOM MODEL FOR MOUSE TUMOR DOSE ASSESSMENT UNDER MV BEAMS , 2011, Health physics.

[113]  K. Camphausen,et al.  Imaging biomarker dynamics in an intracranial murine glioma study of radiation and antiangiogenic therapy. , 2013, International journal of radiation oncology, biology, physics.

[114]  M. Podgorsak,et al.  Dosimetric Calibration and Characterization for Experimental Mouse Thoracic Irradiation Using Orthovoltage X Rays , 2011, Radiation research.

[115]  W. Dörr,et al.  Radiation‐induced variations in urothelial expression of intercellular adhesion molecule 1 (ICAM‐1): association with changes in urinary bladder function , 2004, International journal of radiation biology.

[116]  P. Bunn,et al.  Irradiated nude rat model for orthotopic human lung cancers. , 1991, Cancer research.

[117]  C. Lindquist,et al.  Gamma Knife Radiosurgery. , 1995, Seminars in radiation oncology.

[118]  D. Dolney,et al.  Shielding Considerations for the Small Animal Radiation Research Platform (SARRP) , 2013, Health physics.

[119]  J. Williamson,et al.  High dose-rate brachytherapy treatment delivery: report of the AAPM Radiation Therapy Committee Task Group No. 59. , 1998, Medical physics.

[120]  R. Hill,et al.  Investigations into the role of inflammation in normal tissue response to irradiation. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[121]  J F Williamson,et al.  Code of practice for brachytherapy physics: report of the AAPM Radiation Therapy Committee Task Group No. 56. American Association of Physicists in Medicine. , 1997, Medical physics.

[122]  A. Taghian,et al.  The effect of whole-body irradiation of nude mice on the tumor transplantability and control probability of a human soft tissue sarcoma xenograft. , 1996, Radiation research.

[123]  S. Ikehara,et al.  Optimal protocol for total body irradiation for allogeneic bone marrow transplantation in mice , 2002, Bone Marrow Transplantation.

[124]  A. Alfieri,et al.  STEREOTACTIC RADIOSURGERY IMPROVES LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY IN RATS , 2008, Neurosurgery.

[125]  S. Lehnert,et al.  The use of CT densitometry in the assessment of radiation-induced damage to the rat lung: a comparison with other endpoints. , 1989, International journal of radiation oncology, biology, physics.

[126]  B. Teicher Tumor models for efficacy determination , 2006, Molecular Cancer Therapeutics.

[127]  J. Debus,et al.  Radiation Tolerance of the Rat Spinal Cord after Single and Split Doses of Photons and Carbon Ions1 , 2003, Radiation research.

[128]  Paul J Keall,et al.  Development of a micro-computed tomography-based image-guided conformal radiotherapy system for small animals. , 2010, International journal of radiation oncology, biology, physics.

[129]  K. Yan,et al.  Novel irradiated axial rotational flap model in the rodent. , 2013, JAMA facial plastic surgery.

[130]  Russell H. Taylor,et al.  Towards real-time radiation therapy: GPU accelerated superposition/convolution , 2010, Comput. Methods Programs Biomed..

[131]  M. Bremer,et al.  Radiation protocols determine acute graft-versus-host disease incidence after allogeneic bone marrow transplantation in murine models , 2007, International journal of radiation biology.

[132]  J. Fike,et al.  Apoptosis in the subependyma of young adult rats after single and fractionated doses of X-rays. , 1997, Cancer research.

[133]  Joseph O Deasy,et al.  Feasibility of small animal cranial irradiation with the microRT system. , 2008, Medical physics.

[134]  T D Solberg,et al.  An x-ray image guidance system for small animal stereotactic irradiation , 2010, Physics in medicine and biology.

[135]  D. Grignon,et al.  Neutron or photon irradiation for prostate tumors: enhancement of cytokine therapy in a metastatic tumor model. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[136]  Marc S. Mendonca,et al.  Use of the Leksell Gamma Knife for Localized Small Field Lens Irradiation in Rodents , 2003, Technology in cancer research & treatment.

[137]  R. Kerbel Human Tumor Xenografts as Predictive Preclinical Models for Anticancer Drug Activity in Humans: Better than Commonly Perceived—But They Can Be Improved , 2003, Cancer biology & therapy.