Adenovirus mediated herpes simplex virus-thymidine kinase/ganciclovir gene therapy for resectable malignant glioma

Current Gene Therapy

Volumn 9, Issue 5, 2009, Pages 356-367

  Määttä, Ann Marie ^a   Samaranayake, Haritha ^a,b   Pikkarainen, Jere ^a,b   Wirth, Thomas ^b   Ylä Herttuala, Seppo ^b,c  

^a Finland Ark Therapeutics Oy   (Finland)

^b UNIVERSITY OF EASTERN FINLAND   (Finland)

^c KUOPIO UNIVERSITY HOSPITAL   (Finland)

Author keywords

Adenoviral vector; Bystander effect; Ganciclovir; Gene therapy; Glioma; Herpes simplex virus 1 thymidine kinase

Indexed keywords

ADENOVIRUS VECTOR; BETA GALACTOSIDASE; GANCICLOVIR; HERPESVIRUS VECTOR; THYMIDINE KINASE;

AGITATION; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ANTINEOPLASTIC ACTIVITY; APHASIA; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BILIRUBIN BLOOD LEVEL; BLEEDING; BLOOD PRESSURE; BONE MARROW TOXICITY; BRAIN EDEMA; BRAIN HEMORRHAGE; BYSTANDER EFFECT; CANCER CELL DESTRUCTION; CANCER GENE THERAPY; CANCER GRADING; CANCER RADIOTHERAPY; CANCER SURGERY; CANCER SURVIVAL; CLINICAL TRIAL; CONFUSION; CYTOMEGALOVIRUS INFECTION; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DYSPLASIA; EDEMA; EPILEPTIC STATE; FEVER; GENETIC TRANSDUCTION; GLIOBLASTOMA; GLIOSARCOMA; HEADACHE; HEMATOMA; HEMIPARESIS; HERPES SIMPLEX VIRUS 1; HUMAN; HYDROCEPHALUS; HYPONATREMIA; INTRACRANIAL PRESSURE; LETHARGY; LEUKOCYTE; LEUKOCYTE COUNT; LIQUORRHEA; MENTAL DISEASE; NEUROTOXICITY; NONHUMAN; RASH; RECURRENT CANCER; REVIEW; SARCOMA; SEIZURE; SIDE EFFECT; SUICIDE GENE THERAPY; THROMBOCYTE COUNT; TREATMENT DURATION; TREATMENT RESPONSE; VIRAL GENE DELIVERY SYSTEM;

ADENOVIRIDAE; ANTIVIRAL AGENTS; BRAIN NEOPLASMS; BYSTANDER EFFECT; GANCICLOVIR; GENE THERAPY; GLIOMA; HUMANS; SIMPLEXVIRUS; THYMIDINE KINASE;

ADENOVIRIDAE; HUMAN HERPESVIRUS 1; SIMPLEXVIRUS;

EID: 73449129006     PISSN: 15665232     EISSN: None     Source Type: Journal    
DOI: 10.2174/156652309789753365     Document Type: Review

References (113)

1. Nano R, Ceroni M. The immunobiology of malignant gliomas. Funct Neurol 2005; 20(1): 39-42.
2. Collins VP. Brain tumors: classification and genes. J Neurol Neurosurg Psychiatry 2004; 75 (Suppl 2): ii2-11.
3. Nakamura M, Shimada K, Ishida E, Nakase H, Konishi N. Genetic analysis to complement histopathological diagnosis of brain tumors. Histol Histopathol 2007; 22(3): 327-35.
4. Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 2002; 61(3): 215-25.
5. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004; 64(19): 6892-9.
6. Castro MG, Cowen R, Williamson IK, et al. Current and future strategies for the treatment of malignant brain tumors. Pharmacol Ther 2003; 98(1): 71-108.
7. Pulkkanen KJ, Yla-Herttuala S. Gene therapy for malignant glioma: current clinical status. Mol Ther 2005; 12(4): 585-98.
8. Beduneau A, Saulnier P, Benoit JP. Active targeting of brain tumors using nanocarriers. Biomaterials 2007; 28(33): 4947-67.
9. Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP. Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 2008; 7(1): 71-8.
10. Aghi M, Chiocca EA. Gene therapy for glioblastoma. Neurosurg Focus 2006; 20(4): E18.
11. Lawler SE, Peruzzi PP, Chiocca EA. Genetic strategies for brain tumor therapy. Cancer Gene Ther 2006; 13(3): 225-33.
12. King GD, Curtin JF, Candolfi M, Kroeger K, Lowenstein PR, Castro MG. Gene therapy and targeted toxins for glioma. Curr Gene Ther 2005; 5(6): 535-57.
13. No authors listed. Phase I study of cytokine-gene modified autologous neuroblastoma cells for treatment of relapsed/refractory neuroblastoma. Hum Gene Ther 1992; 3(6): 665-76.
14. Oldfield EH, Ram Z, Culver KW, Blaese RM, DeVroom HL, Anderson WF. Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum Gene Ther 1993; 4(1): 39-69.
15. Ram Z, Culver KW, Oshiro EM, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 1997; 3(12): 1354-61.
16. Klatzmann D, Valery CA, Bensimon G, et al. A phase I/II study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma. Hum Gene Ther 1998; 9(17): 2595-604.
17. McKnight SL. The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Res 1980; 8(24): 5949-64.
18. Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986; 46(10): 5276-81.
19. Moolten FL, Wells JM. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 1990; 82(4): 297-300.
20. Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 1992; 256(5063): 1550-2.
21. Ram Z, Culver KW, Walbridge S, Blaese RM, Oldfield EH. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res 1993; 53(1): 83-8.
22. Palmer DH, Young LS, Mautner V. Cancer gene-therapy: clinical trials. Trends Biotechnol 2006; 24(2): 76-82.
23. Aghi M, Hochberg F, Breakefield XO. Prodrug activation enzymes in cancer gene therapy. J Gene Med 2000; 2(3): 148-64.
24. McGuirt PV, Furman PA. Acyclovir inhibition of viral DNA chain elongation in herpes simplex virus-infected cells. Am J Med 1982; 73(1A): 67-71.
25. Cheng YC, Grill SP, Dutschman GE, Nakayama K, Bastow KF. Metabolism of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new anti-herpes virus compound, in herpes simplex virus-infected cells. J Biol Chem 1983; 258(20): 12460-4.
26. Freeman SM, Abboud CN, Whartenby KA, et al. The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53(21): 5274-83.
27. Beltinger C, Fulda S, Kammertoens T, Meyer E, Uckert W, Debatin KM. Herpes simplex virus thymidine kinase/ganciclovirinduced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc Natl Acad Sci USA 1999; 96(15): 8699-704.
28. Kianmanesh AR, Perrin H, Panis Y, et al. A "distant" bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Hum Gene Ther 1997; 8(15): 1807-14.
29. Vile RG, Castleden S, Marshall J, Camplejohn R, Upton C, Chong H. Generation of an anti-tumor immune response in a non-immunogenic tumor: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoral cytokine expression. Int J Cancer 1997; 71(2): 267-74.
30. Barba D, Hardin J, Sadelain M, Gage FH. Development of antitumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc Natl Acad Sci USA 1994; 91(10): 4348-52.
31. Rainov NG, Kramm CM, Banning U, et al. Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme. Gene Ther 2000; 7(21): 1853-8.
32. Dewey RA, Morrissey G, Cowsill CM, et al. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. Nat Med 1999; 5(11): 1256-63.
33. Wu JK, Cano WG, Meylaerts SA, Qi P, Vrionis F, Cherington V. Bystander tumoricidal effect in the treatment of experimental brain tumors. Neurosurgery 1994; 35(6): 1094-102.
34. Sandmair AM, Turunen M, Tyynela K, et al. Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model: effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissue reactions. Cancer Gene Ther 2000; 7(3): 413-21.
35. Rubsam LZ, Boucher PD, Murphy PJ, KuKuruga M, Shewach DS. Cytotoxicity and accumulation of ganciclovir triphosphate in bystander cells cocultured with herpes simplex virus type 1 thymidine kinase-expressing human glioblastoma cells. Cancer Res 1999; 59(3): 669-75.
36. Namba H, Iwadate Y, Tagawa M, et al. Evaluation of the bystander effect in experimental brain tumors bearing herpes simplex virus-thymidine kinase gene by serial magnetic resonance imaging. Hum Gene Ther 1996; 7(15): 1847-52.
37. Caruso M, Panis Y, Gagandeep S, Houssin D, Salzmann JL, Klatzmann D. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc Natl Acad Sci USA 1993; 90(15): 7024-8.
38. Burrows FJ, Gore M, Smiley WR, et al. Purified herpes simplex virus thymidine kinase retroviral particles: III. Characterization of bystander killing mechanisms in transfected tumor cells. Cancer Gene Ther 2002; 9(1): 87-95.
39. Ishii-Morita H, Agbaria R, Mullen CA, et al. Mechanism of 'bystander effect' killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment. Gene Ther 1997; 4(3): 244-51.
40. Touraine RL, Vahanian N, Ramsey WJ, Blaese RM. Enhancement of the herpes simplex virus thymidine kinase/ganciclovir bystander effect and its antitumor efficacy in vivo by pharmacologic manipulation of gap junctions. Hum Gene Ther 1998; 9(16): 2385-91.
41. Mesnil M, Piccoli C, Tiraby G, Willecke K, Yamasaki H. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci USA 1996; 93(5): 1831-5.
42. Elshami AA, Saavedra A, Zhang H, et al. Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther 1996; 3(1): 85-92.
43. Dilber MS, Abedi MR, Christensson B, et al. Gap junctions promote the bystander effect of herpes simplex virus thymidine kinase in vivo. Cancer Res 1997; 57(8): 1523-8.
44. Bi WL, Parysek LM, Warnick R, Stambrook PJ. In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum Gene Ther 1993; 4(6): 725-31.
45. Asklund T, Appelskog IB, Ammerpohl O, et al. Gap junction-mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSVtk gene. Exp Cell Res 2003; 284(2): 185-95.
46. Kruse CA, Lamb C, Hogan S, Smiley WR, Kleinschmidt-Demasters BK, Burrows FJ. Purified herpes simplex thymidine kinase retroviral particles. II. Influence of clinical parameters and bystander killing mechanisms. Cancer Gene Ther 2000; 7(1): 118-27.
47. Colombo BM, Benedetti S, Ottolenghi S, et al. The "bystander effect": association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. Hum Gene Ther 1995; 6(6): 763-72.
48. Ram Z, Walbridge S, Shawker T, Culver KW, Blaese RM, Oldfield EH. The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. J Neurosurg 1994; 81(2): 256-60.
49. Hamel W, Magnelli L, Chiarugi VP, Israel MA. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res 1996; 56(12): 2697-702.
50. Izquierdo M, Cortes M, de Felipe P, et al. Long-term rat survival after malignant brain tumor regression by retroviral gene therapy. Gene Ther 1995; 2(1): 66-9.
51. Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 1994; 91(8): 3054-7.
52. Maron A, Gustin T, Le Roux A, et al. Gene therapy of rat C6 glioma using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene: long-term follow-up by magnetic resonance imaging. Gene Ther 1996; 3(4): 315-22.
53. Rainov NG, Kramm CM, boody-Guterman K, et al. Retrovirus-mediated gene therapy of experimental brain neoplasms using the herpes simplex virus-thymidine kinase/ganciclovir paradigm. Cancer Gene Ther 1996; 3(2): 99-106.
54. Vincent AJ, Vogels R, Someren GV, et al. Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. Hum Gene Ther 1996; 7(2): 197-205.
55. Tyynela K, Sandmair AM, Turunen M, et al. Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model. Cancer Gene Ther 2002; 9(11): 917-24.
56. Perez-Cruet MJ, Trask TW, Chen SH, et al. Adenovirus-mediated gene therapy of experimental gliomas. J Neurosci Res 1994; 39(4): 506-11.
57. Maatta AM, Tenhunen A, Pasanen T, et al. Non-small cell lung cancer as a target disease for herpes simplex type 1 thymidine kinase-ganciclovir gene therapy. Int J Oncol 2004; 24(4): 943-9.
58. Pulkkanen KJ, Parkkinen JJ, Laukkanen JM, et al. HSV-tk gene therapy for human renal cell carcinoma in nude mice. Cancer Gene Ther 2001; 8(7): 529-36.
59. Sterman DH, Treat J, Litzky LA, et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998; 9(7): 1083-92.
60. Wiewrodt R, Amin K, Kiefer M, et al. Adenovirus-mediated gene transfer of enhanced Herpes simplex virus thymidine kinase mutants improves prodrug-mediated tumor cell killing. Cancer Gene Ther 2003; 10(5): 353-64.
61. Ayala G, Satoh T, Li R, et al. Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer. Mol Ther 2006; 13(4): 716-28.
62. Sandmair AM, Loimas S, Puranen P, et al. Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther 2000; 11(16): 2197-205.
63. Valerie K, Hawkins W, Farnsworth J, et al. Substantially improved in vivo radiosensitization of rat glioma with mutant HSV-TK and acyclovir. Cancer Gene Ther 2001; 8(1): 3-8.
64. Rainov NG, Fels C, Droege JW, Schafer C, Kramm CM, Chou TC. Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma. Cancer Gene Ther 2001; 8(9): 662-8.
65. Wahlfors T, Hakkarainen T, Janne J, Alhonen L, Wahlfors J. In vivo enhancement of herpes simplex virus thymidine kinase/ ganciclovir cancer gene therapy with polyamine biosynthesis inhibition. Int J Cancer 2006; 118(11): 2907-10.
66. Benedetti S, Dimeco F, Pollo B, et al. Limited efficacy of the HSV-TK/ GCV system for gene therapy of malignant gliomas and perspectives for the combined transduction of the interleukin-4 gene. Hum Gene Ther 1997; 8(11): 1345-53.
67. Ali S, King GD, Curtin JF, et al. Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. Cancer Res 2005; 65(16): 7194-204.
68. Nanda D, Vogels R, Havenga M, Avezaat CJ, Bout A, Smitt PS. Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. Cancer Res 2001; 61(24): 8743-50.
69. Shine HD, Wyde PR, guilar-Cordova E, et al. Neurotoxicity of intracerebral injection of a replication-defective adenoviral vector in a semipermissive species (cotton rat). Gene Ther 1997; 4(4): 275-9.
70. Driesse MJ, Vincent AJ, Sillevis SPA, et al. Intracerebral injection of adenovirus harboring the HSVtk gene combined with ganciclovir administration: toxicity study in nonhuman primates. Gene Ther 1998; 5(8): 1122-9.
71. Driesse MJ, Esandi MC, Kros JM, et al. Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity. Gene Ther 2000; 7(16): 1401-9.
72. Verma IM, Weitzman MD. Gene therapy: twenty-first century medicine. Annu Rev Biochem 2005; 74: 711-38.
73. Somia N, Verma IM. Gene therapy: trials and tribulations. Nat Rev Genet 2000; 1(2): 91-9.
74. Ketola A, Maatta AM, Pasanen T, Tulimaki K, Wahlfors J. Osteosarcoma and chondrosarcoma as targets for virus vectors and herpes simplex virus thymidine kinase/ganciclovir gene therapy. Int J Mol Med 2004; 13(5): 705-10.
75. Maatta AM, Korja S, Venhoranta H, et al. Transcriptional targeting of virus-mediated gene transfer by the human hexokinase II promoter. Int J Mol Med 2006; 18(5): 901-8.
76. Uch R, Gerolami R, Faivre J, et al. Hepatoma cell-specific ganciclovir-mediated toxicity of a lentivirally transduced HSV-TkEGFP fusion protein gene placed under the control of rat alphafetoprotein gene regulatory sequences. Cancer Gene Ther 2003; 10(9): 689-95.
77. Su H, Lu R, Chang JC, Kan YW. Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice. Proc Natl Acad Sci USA 1997; 94(25): 13891-6.
78. Okada H, Miyamura K, Itoh T, et al. Gene therapy against an experimental glioma using adeno-associated virus vectors. Gene Ther 1996; 3(11): 957-64.
79. Kun LE, Gajjar A, Muhlbauer M, et al. Stereotactic injection of herpes simplex thymidine kinase vector producer cells (PA317-G1Tk1SvNa.7) and intravenous ganciclovir for the treatment of progressive or recurrent primary supratentorial pediatric malignant brain tumors. Hum Gene Ther 1995; 6(9): 1231-55.
80. Raffel C, Culver K, Kohn D, et al. Gene therapy for the treatment of recurrent pediatric malignant astrocytomas with in vivo tumor transduction with the herpes simplex thymidine kinase gene/ ganciclovir system. Hum Gene Ther 1994; 5(7): 863-90.
81. Shand N, Weber F, Mariani L, et al. A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group. Hum Gene Ther 1999; 10(14): 2325-35.
82. Packer RJ, Raffel C, Villablanca JG, et al. Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration. J Neurosurg 2000; 92(2): 249-54.
83. Valery CA, Seilhean D, Boyer O, et al. Long-term survival after gene therapy for a recurrent glioblastoma. Neurology 2002; 58(7): 1109-12.
84. Palu G, Cavaggioni A, Calvi P, et al. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: a pilot study in humans. Gene Ther 1999; 6(3): 330-7.
85. Trask TW, Trask RP, Aguilar-Cordova E, et al. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther 2000; 1(2): 195-203.
86. Puumalainen AM, Vapalahti M, Agrawal RS, et al. Betagalactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 1998; 9(12): 1769-74.
87. Harsh GR, Deisboeck TS, Louis DN, et al. Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a genemarking and neuropathological study. J Neurosurg 2000; 92(5): 804-11.
88. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 2000; 11(17): 2389-401.
89. Immonen A, Vapalahti M, Tyynela K, et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 2004; 10(5): 967-72.
90. nd ed. San Diego: Academic Press 2002; pp. 505-11.
91. Germano IM, Fable J, Gultekin SH, Silvers A. Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 2003; 65(3): 279-89.
92. Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C. Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther 2003; 7(6): 851-8.
93. Hakkarainen T, Hemminki A, Curiel DT, Wahlfors J. A conditionally replicative adenovirus that codes for a TK-GFP fusion protein (Ad5Delta24TK-GFP) for evaluation of the potency of oncolytic virotherapy combined with molecular chemotherapy. Int J Mol Med 2006; 18(4): 751-9.
94. Vile R, Ando D, Kirn D. The oncolytic virotherapy treatment platform for cancer: unique biological and biosafety points to consider. Cancer Gene Ther 2002; 9(12): 1062-7.
95. Working PK, Lin A, Borellini F. Meeting product development challenges in manufacturing clinical grade oncolytic adenoviruses. Oncogene 2005; 24(52): 7792-801.
96. Lowenstein PR, Mandel RJ, Xiong WD, Kroeger K, Castro MG. Immune responses to adenovirus and adeno-associated vectors used for gene therapy of brain diseases: the role of immunological synapses in understanding the cell biology of neuroimmune interactions. Curr Gene Ther 2007; 7(5): 347-60.
97. Krex D, Klink B, Hartmann C, et al. Long-term survival with glioblastoma multiforme. Brain 2007; 130(Pt 10): 2596-606.
98. McCormack BM, Miller DC, Budzilovich GN, Voorhees GJ, Ransohoff J. Treatment and survival of low-grade astrocytoma in adults - 1977-1988. Neurosurgery 1992; 31(4): 636-42.
99. Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol 2005; 109(1): 93-108.
100. Shirahata M, Iwao-Koizumi K, Saito S, et al. Gene expression-based molecular diagnostic system for malignant gliomas is superior to histological diagnosis. Clin Cancer Res 2007; 13(24): 7341-56.
101. Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 1997; 79(7): 1381-93.
102. Louis DN, Holland EC, Cairncross JG. Glioma classification: a molecular reappraisal. Am J Pathol 2001; 159(3): 779-86.
103. Freije WA, Castro-Vargas FE, Fang Z, et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res 2004; 64(18): 6503-10.
104. Tait MJ, Petrik V, Loosemore A, Bell BA, Papadopoulos MC. Survival of patients with glioblastoma multiforme has not improved between 1993 and 2004: analysis of 625 cases. Br J Neurosurg 2007; 21(5): 496-500.
105. Chaichana KL, McGirt MJ, Frazier J, Attenello F, Guerrero-Cazares H, Quinones-Hinojosa A. Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection. J Neurooncol 2008; 89(2): 219-24.
106. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002; 359(9311): 1011-8.
107. Anderson E, Grant R, Lewis SC, Whittle IR. Randomized phase III controlled trials of therapy in malignant glioma: where are we after 40 years? Br J Neurosurg 2008; 22(3): 339-49.
108. Aldape K, Colman H, James D. Models of malignant glioma. Drug Discov Today 2006; 3(2): 191-6.
109. Laerum OD, Rajewsky MF. Neoplastic transformation of fetal rat brain cells in culture after exposure to ethylnitrosourea in vivo. J Natl Cancer Inst 1975; 55(5): 1177-87.
110. Laerum OD, Rajewsky MF, Schachner M, Stavrou D, Haglid KG, Haugen A. Phenotypic properties of neoplastic cell lines developed from fetal rat brain cells in culture after exposure to ethylnitrosourea in vivo. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1977; 89(3): 273-95.
111. Ramadan MA, Wechsler W. Transplacental induction of neurogenic tumors in BD IX rats by intragastric administration of ethyl-nitrosourea precursors. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1975; 84(2): 177-87.
112. Bulnes-Sesma S, Ullibarri-Ortiz de Zarate N, Lafuente-Sanchez JV. [Tumor induction by ethylnitrosourea in the central nervous system]. Rev Neurol 2006; 43(12): 733-8.
113. King GD, Muhammad AK, Curtin JF, et al. Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model. Neuro Oncol 2008; 10(1): 19-31.