Experimental Radiosurgery Models

  • Ajay Niranjan
  • Douglas Kondziolka


The field of stereotactic radiosurgery represents one of the fundamental shifts in neurologic surgery over the past two decades. Compared with conventional invasive surgery techniques, radiosurgery is minimally invasive and relies on biological response of tissues in order to eradicate or inactivate them. Radiosurgery is conceptually different from fractionated radiation therapy. The efficacy of large-field fractionated radiotherapy to treat brain tumors is dependent on biological differences between normal and tumor cells. Fractionated radiotherapy exploits these differences to limit the risk of normal tissue injury in patients with malignant brain tumors, thus it can increase the therapeutic ratio, which is equivalent to the rate of tumor control divided by the rate of complications.


Trigeminal Neuralgia Gamma Knife Stereotactic Radiosurgery Malignant Brain Tumor Suicide Gene Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Larsson B, Leksell L, Rexed B, et al. The high-energy proton beam as neurosurgical tool. Nature 1958; 182(6):1222–1223.CrossRefPubMedGoogle Scholar
  2. 2.
    Rexed B, Mair W, Sourander P, et al. Effect of high-energy protons on the rabbit. Acta Radiol Oncol Radiat Phys Biol 1960; 53:289–299.Google Scholar
  3. 3.
    Leksell L, Larsson B, Anderson B, et al. Lesions in the depth of the brain produced by a beam of high-energy protons. Acta Radiol Ther Phys Biol 1960; 53:251–264.Google Scholar
  4. 4.
    Andersson B, Larsson B, Leksell L, et al. Histopathology of late local radiolesions in the goat brain. Acta Radiol Ther Phys Biol 1970; 9(5):385–394.PubMedGoogle Scholar
  5. 5.
    Nilsson A, Wennerstrand J, Leksell D, et al. Stereotactic gamma irradiation of basilar artery in cat. Preliminary experiences. Acta Radiol Oncol Radiat Phys Biol 1978; 17(2):150–160.PubMedGoogle Scholar
  6. 6.
    Calvo W, Hopewell JW, Reinhold HS, et al. Time-and dose-related changes in the white matter of the rat brain after single doses of X rays. Br J Radiol 1988; 61:1043–1052.CrossRefPubMedGoogle Scholar
  7. 7.
    Fike J, Gobbel G. Central nervous system radiation injury in large animal models. In: Gutin P, Leibel S, Sheline G, eds. Radiation Injury to the Nervous System. New York: Raven Press; 1991:113–135.Google Scholar
  8. 8.
    van der Kogel A. Central nervous sytem radiation injury in small animal models. In: Gutin P, Leibel S, Sheline G, eds. Radiation Injury to the Nervous System. New York: Raven Press; 1991:113–135.Google Scholar
  9. 9.
    Calvo W, Hopewell J, Reinhold H, et al. Dose-dependent and time-dependent changes in the choroid plexus of the irradiated rat brain. Br J Radiol 1987; 60:1109–1117.CrossRefPubMedGoogle Scholar
  10. 10.
    Hopewell J, Calvo W, Campling D, et al. The role of the vasculature in normal tissue responses. In: Fielden E, Fowler J, Hendry J, Scott D, eds. Radiation Research, Proceedings of the 8th International Congress of Radiation Research. London: Taylor & Francis; 1987:789–794.Google Scholar
  11. 11.
    Zeman W, Samorajski T. Effects of irradiation on the nervous system. In: Berdjis CC, ed. Pathology of Irradiation. Baltimore: Williams & Wilkins, 1971:213–277.Google Scholar
  12. 12.
    Hopewell JW, Wright EA. The nature of latent cerebral irradiation damage and it modification by hypertension. Br J Radiol 1970; 43:161–167.CrossRefPubMedGoogle Scholar
  13. 13.
    Reinhold H, Hopewell J. Late changes in the architecture of blood vessels of the rat brain after irradiation. Br J Radiol 1980; 53:693–696.CrossRefPubMedGoogle Scholar
  14. 14.
    Schultheiss T, Stephens L. Permanent radiation myelopathy. Br J Radiol 1992; 65:737–753.CrossRefPubMedGoogle Scholar
  15. 15.
    Lunsford LD, Altschuler EM, Flickinger JC, et al. In vivo biological effects of stereotactic radiosurgery: a primate model. Neurosurgery 1990; 27(3):373–382.CrossRefPubMedGoogle Scholar
  16. 16.
    Kondziolka D, Lunsford LD, Altschuler EM, et al. Biological effects of stereotactic radiosurgery in the normal primate brainstem. In: Lunsford LD, ed. Stereotactic Radiosurgery Update. New York: Elsevier; 1992:291–294.Google Scholar
  17. 17.
    Kondziolka D, Lunsford LD, Claassen D, et al. Radiobiology of radiosurgery: Part I. The normal rat brain model. Neurosurgery 1992; 31(2):271–279.PubMedGoogle Scholar
  18. 18.
    Blatt DR, Friedman WA, Bova FJ, et al. Temporal characteristics of radiosurgical lesions in an animal model. J Neurosurg 1994; 80(6):1046–1055.CrossRefPubMedGoogle Scholar
  19. 19.
    Kamiryo T, Kassell NF, Thai QA, et al. Histological changes in the normal rat brain after gamma irradiation. Acta Neurochir (Wien) 1996; 138(4):451–459.CrossRefGoogle Scholar
  20. 20.
    Hopewell JW, Wright EA. The effects of dose and field size on late radiation damage to the rat spinal cord. Int J Radiat Biol Relat Stud Phys Chem Med 1975; 28(4):325–333.CrossRefPubMedGoogle Scholar
  21. 21.
    Karger CP, Munter MW, Heiland S, et al. Dose-response curves and tolerance doses for late functional changes in the normal rat brain after stereotactic radiosurgery evaluated by magnetic resonance imaging: influence of end points and follow-up time. Radiat Res 2002; 157(6):617–625.CrossRefPubMedGoogle Scholar
  22. 22.
    Kamiryo T, Lopes MB, Kassell NF, et al. Radiosurgery-induced microvascular alterations precede necrosis of the brain neuropil. Neurosurgery 2001; 49(2):409–414; discussion 14–15.CrossRefPubMedGoogle Scholar
  23. 23.
    Oldfield EH, Friedman R, Kinsella T, et al. Reduction in radiation-induced brain injury by use of pentobarbital or lidocaine protection. J Neurosurg 1990; 72(5):737–744.CrossRefPubMedGoogle Scholar
  24. 24.
    Smith SL, Scherch HM, Hall ED. Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury. J Neurosurg 1996; 84(2):229–233.CrossRefPubMedGoogle Scholar
  25. 25.
    Braughler JM. Lipid peroxidation-induced inhibition of gamma-aminobutyric acid uptake in rat brain synaptosomes: protection by glucocorticoids. J Neurochem 1985; 44(4):1282–1288.CrossRefPubMedGoogle Scholar
  26. 26.
    Bernstein M, Ginsberg H, Glen J. Protection of iodine-125 brachy-therapy brain injury in the rat with the 21-aminosteroid U-74389F. Neurosurgery 1992; 31(5):923–927; discussion 7–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Buatti JM, Friedman WA, Theele DP, et al. The lazaroid U74389G protects normal brain from stereotactic radiosurgery-induced radiation injury. Int J Radiat Oncol Biol Phys 1996; 34(3):591–597.PubMedGoogle Scholar
  28. 28.
    Kondziolka D, Somaza S, Martinez AJ, et al. Radioprotective effects of the 21-aminosteroid U-74389G for stereotactic radiosurgery. Neurosurgery 1997; 41(1):203–208.CrossRefPubMedGoogle Scholar
  29. 29.
    Staba MJ, Mauceri HJ, Kufe DW, et al. Adenoviral TNF-alpha gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft. Gene Therapy 1998; 5(3):293–300.CrossRefPubMedGoogle Scholar
  30. 30.
    Cao G, Kuriyama S, Du P, et al. Complete regression of established murine hepatocellular carcinoma by in vivo tumor necrosis factor alpha gene transfer.[comment]. Gastroenterology 1997; 112(2):501–510.CrossRefPubMedGoogle Scholar
  31. 31.
    Han SK, Brody SL, Crystal RG. Suppression of in vivo tumorigenicity of human lung cancer cells by retrovirus-mediated transfer of the human tumor necrosis factor-alpha cDNA. Am J Respir Cell Mol Biol 1994; 11(3):270–278.PubMedGoogle Scholar
  32. 32.
    Ostensen ME, Thiele DL, Lipsky PE. Enhancement of human natural killer cell function by the combined effects of tumor necrosis factor alpha or interleukin-1 and interferon-alpha or interleukin-2. J Biol Response Modifiers 1989; 8(1):53–61.Google Scholar
  33. 33.
    Owen-Schaub LB, Gutterman JU, Grimm EA. Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor alpha and interleukin 2 in the generation of human lymphokine-activated killer cell cytotoxicity. Cancer Res 1988;48(4):788–792.PubMedGoogle Scholar
  34. 34.
    Gridley DS, Archambeau JO, Andres MA, et al. Tumor necrosis factor-alpha enhances antitumor effects of radiation against glioma xenografts. Oncol Res 1997; 9(5):217–227.PubMedGoogle Scholar
  35. 35.
    Niranjan A, Moriuchi S, Lunsford LD, et al. Effective treatment of experimental glioblastoma by HSV vector-mediated TNF alpha and HSV-tk gene transfer in combination with radiosurgery and ganciclovir administration. Mol Ther 2000; 2(2):114–120.CrossRefPubMedGoogle Scholar
  36. 36.
    Marconi P, Tamura M, Moriuchi S, et al. Connexin 43-enhanced suicide gene therapy using herpesviral vectors. Mol Ther 2000; 1(1):71–81.CrossRefPubMedGoogle Scholar
  37. 37.
    Moriuchi S, Oligino T, Krisky D, et al. Enhanced tumor cell killing in the presence of ganciclovir by herpes simplex virus type 1 vector-directed coexpression of human tumor necrosis factor-alpha and herpes simplex virus thymidine kinase. Cancer Res 1998; 58(24):5731–5737.PubMedGoogle Scholar
  38. 38.
    Kondziolka D, Lunsford LD, Claassen D, et al. Radiobiology of radiosurgery: Part II. The rat C6 glioma model. Neurosurgery 1992; 31(2):280–287; discussion 7–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Kondziolka D, Mori Y, Martinez AJ, et al. Beneficial effects of the radioprotectant 21-aminosteroid U-74389G in a radiosurgery rat malignant glioma model. Int J Radiat Oncol Bio Phys 1999; 44(1):179–184.CrossRefGoogle Scholar
  40. 40.
    Nakahara N, Okada H, Witham TF, et al. Combination of stereotactic radiosurgery and cytokine gene-transduced tumor cell vaccination: a new strategy against metastatic brain tumors. J Neurosurg 2001; 95(6):984–989.CrossRefPubMedGoogle Scholar
  41. 41.
    Niranjan A, Wolfe D, Tamura M, et al. Treatment of rat gliosarcoma brain tumors by HSV-based multigene therapy combined with radiosurgery. Mol Ther 2003; 8(8):530–542.CrossRefPubMedGoogle Scholar
  42. 42.
    Mori Y, Kondziolka D, Balzer J, et al. Effects of stereotactic radiosurgery on an animal model of hippocampal epilepsy. Neurosurgery 2000; 46(1):157–165; discussion 65–68.CrossRefPubMedGoogle Scholar
  43. 43.
    Maesawa S, Kondziolka D, Dixon CE, et al. Subnecrotic stereotactic radiosurgery controlling epilepsy produced by kainic acid injection in rats. J Neurosurg 2000; 93(6):1033–1040.CrossRefPubMedGoogle Scholar
  44. 44.
    Liscak R, Vladyka V, Novotny J Jr, et al. Leksell gamma knife lesioning of the rat hippocampus: the relationship between radiation dose and functional and structural damage. J Neurosurg 2002; 97(5 Suppl):666–673.PubMedGoogle Scholar
  45. 45.
    De Salles AA, Melega WP, Lacan G, et al. Radiosurgery performed with the aid of a 3-mm collimator in the subthalamic nucleus and substantia nigra of the vervet monkey. J Neurosurg 2001; 95(6):990–997.CrossRefPubMedGoogle Scholar
  46. 46.
    Kondziolka D, Conce M, Niranjan A, et al. Histology of the 100 Gy thalomotomy in the baboon. Radiosurgery 2002; 4(4):279–284.CrossRefGoogle Scholar
  47. 47.
    Kondziolka D, Lacomis D, Niranjan A, et al. Histological effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery. Neurosurgery 2000; 46(4):971–976; discussion 6–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Ishikawa S, Otsuki T, Kaneki M, et al. Dose-related effects of single focal irradiation in the medial temporal lobe structures in rats—magnetic resonance imaging and histological study. Neurol Med Chir (Tokyo) 1999; 39(1):1–7.CrossRefGoogle Scholar
  49. 49.
    Chen ZF, Kamiryo T, Henson SL, et al. Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats. J Neurosurg 2001; 94(2):270–280.CrossRefPubMedGoogle Scholar
  50. 50.
    Zerris VA, Zheng Z, Noren G, et al. Radiation and regeneration: behavioral improvement and GDNF expression after Gamma Knife radiosurgery in the 6-OHDA rodent model of hemi-parkinsonism. Acta Neurochir Suppl 2002; 84:99–105.PubMedGoogle Scholar
  51. 51.
    Brisman JL, Cole AJ, Cosgrove GR, et al. Radiosurgery of the rat hippocampus: magnetic resonance imaging, neurophysiological, histological, and behavioral studies. Neurosurgery 2003; 53(4):951–961; discussion 61–62.CrossRefPubMedGoogle Scholar
  52. 52.
    Vincent DA, Alden TD, Kamiryo T, et al. The baromodulatory effect of gamma knife irradiation of the hypothalamus in the obese Zucker rat. Stereotact Funct Neurosurg 2005; 83(1):6–11.CrossRefPubMedGoogle Scholar
  53. 53.
    Tada E, Yang C, Gobbel GT, et al. Long-term impairment of subependymal repopulation following damage by ionizing irradiation. Exp Neurol 1999; 160(1):66–77.CrossRefPubMedGoogle Scholar
  54. 54.
    Tada E, Parent JM, Lowenstein DH, et al. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 2000; 99(1):33–41.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ajay Niranjan
    • 1
  • Douglas Kondziolka
    • 1
  1. 1.University of PittsburghPittsburghUSA

Personalised recommendations