View More View Less
  • 1 II. sz. Gyermekgyógyászati Klinika, Semmelweis Egyetem ÁOK, 1094, Budapest, Tűzoltó utca 7–9.
Restricted access

Absztrakt

A medulloblastoma az egyik leggyakoribb gyermekkori agydaganat. Mortalitása az utóbbi évtizedekben jelentősen csökkent, mely a sebészi és radioterápiás kezelésen kívül jelentős mértékben a gyógyszeres terápia fejlődésének köszönhető. E közlemény célja a gyógyszeres kezelés jelenleg alkalmazott formáinak kritikus áttekintése és azon próbálkozások megemlítése, melyek a tumor molekuláris genetikai alapjai felől kiindulva kísérlik meg a jelenlegi terápia továbbfejlesztését.

  • 1. TJ Abouantoun TJ Macdonald 2009 Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor Mol Cancer Ther 5 1137 1147.

    • Search Google Scholar
    • Export Citation
  • 2. N Ahmed M Ratnayake B Savoldo 2007 Regression of experimental medulloblastoma following transfer of HER2-specific T cells Cancer Res 67 5957 5964.

    • Search Google Scholar
    • Export Citation
  • 3. JA Anderton JC Lindsey ME Lusher 2008 Global analysis of the medulloblastoma epigenome identifies disease-subgroup-specific inactivation of COL1A2 Neuro Oncol 10 981 994.

    • Search Google Scholar
    • Export Citation
  • 4. N Baryawno B Sveinbjörnsson S Eksborg 2008 Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets Neuro Oncol 10 661 674.

    • Search Google Scholar
    • Export Citation
  • 5. T Blom A Roselli V Häyry 2010 Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors J Neurooncol 97 217 224.

    • Search Google Scholar
    • Export Citation
  • 6. B Bodey V Bodey SE Siegel HE Kaiser 2004 Survivin expression in childhood medulloblastomas: a possible diagnostic and prognostic marker In Vivo 18 713 718.

    • Search Google Scholar
    • Export Citation
  • 7. GA Calin CM Croce 2006 MicroRNA signatures in human cancers Nat Rev Cancer 11 857 866.

  • 8. I Casanova R Bosch A Lasa 2008 A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cells Int J Cancer 123 217 226.

    • Search Google Scholar
    • Export Citation
  • 9. Q Chang Z Chen J You 2007 All-trans-retinoic acid induces cell growth arrest in a human medulloblastoma cell line J Neurooncol 84 263 267.

    • Search Google Scholar
    • Export Citation
  • 10. P Chastagner E Bouffet J Grill C Kalifa 2001 What have we learnt from previous phase II trials to help in the management of childhood brain tumours? Eur J Cancer 37 1981 1993.

    • Search Google Scholar
    • Export Citation
  • 11. KJ Cheung BL Ebert 2009 Therapeutic potential of targeting haploinsufficient genes in cancer Pediatr Blood Cancer 53 136 144.

  • 12. S Chilton-Macneill M Ho C Hawkins 2004 C-kit expression and mutational analysis in medulloblastoma Pediatr Dev Pathol 7 493 498.

  • 13. SN Chi SL Gardner AS Levy 2004 Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma J Clin Oncol 22 4881 4887.

    • Search Google Scholar
    • Export Citation
  • 14. EK Curran KL Sainani GM Le 2009 Gender affects survival for medulloblastoma only in older children and adults: a study from the Surveillance Epidemiology and End Results Registry Pediatr Blood Cancer 52 60 64.

    • Search Google Scholar
    • Export Citation
  • 15. G Dabasi P Hauser GP Kertész 2007 Gyermekkori agytumorok vizsgálata szomatosztatin-analóg (111ln-DTPA-D-Phe1-octreotide) alkalmazásával Magyar Onkológia 51 229 234.

    • Search Google Scholar
    • Export Citation
  • 16. G Dhall H Grodman L Ji 2008 Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols Pediatr Blood Cancer 50 1169 1175.

    • Search Google Scholar
    • Export Citation
  • 17. C Di S Liao DC Adamson 2005 Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid Cancer Res 65 919 924.

    • Search Google Scholar
    • Export Citation
  • 18. PB Dirks 2008 Brain tumor stem cells: bringing order to the chaos of brain cancer J Clin Oncol 26 2916 2924.

  • 19. AA Dlugosz M Talpaz 2009 Following the hedgehog to new cancer therapies N Engl J Med 361 1202 1205.

  • 20. JR Downing 2009 Cancer genomes – continuing progress N Engl J Med 361 1111 1112.

  • 21. RG Dumitrescu 2009 Epigenetic targets in cancer epidemiology Methods Mol Biol 471 457 467.

  • 22. SL Emanuel TV Hughes M Adams 2008 Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors Mol Pharmacol 73 338 348.

    • Search Google Scholar
    • Export Citation
  • 23. X Fan CG Eberhart 2008 Medulloblastoma stem cells J Clin Oncol 26 2821 2827.

  • 24. E Ferretti E De Smaele A Po 2009 MicroRNA profiling in human medulloblastoma Int J Cancer 124 568 577.

  • 25. GN Fuller X Su RE Price 2005 Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP-16 Mol Cancer Ther 4 343 349.

    • Search Google Scholar
    • Export Citation
  • 26. AM Fulton X Ma N Kundu 2006 Targeting prostaglandin E EP receptors to inhibit metastasis Cancer Res 66 9794 9797.

  • 27. A Gajjar R Hernan M Kocak 2004 Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma J Clin Oncol 22 984 993.

    • Search Google Scholar
    • Export Citation
  • 28. NG Gottardo A Gajjar 2008 Chemotherapy for malignant brain tumors of childhood J Child Neurol 23 1149 1159.

  • 29. NG Gottardo A Gajjar 2006 Current therapy for medulloblastoma Curr Treat Options Neurol 8 319 334.

  • 30. Gurney JG , Smith MA, Bunin GR. CNS and miscellaneous intracranial and intraspinal neoplasms. In: Cancer incidence and survival among children and adolescents: Bethesda, MD: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. Eds.: Ries LAG, Smith MA, Gurney JG, et al. NIH Pub No 99-4649, 1999, pp. 5163.

    • Search Google Scholar
    • Export Citation
  • 31. J Guyotat J Champier GS Pierre 2001 Differential expression of somatostatin receptors in medulloblastoma J Neurooncol 51 93 103.

  • 32. T Harder A Plagemann A Harder 2008 Birth weight and subsequent risk of childhood primary brain tumors: a meta-analysis Am J Epidemiol 168 366 373.

    • Search Google Scholar
    • Export Citation
  • 33. NJ Harding JM Birch SJ Hepworth PA McKinney 2009 Infectious exposure in the first year of life and risk of central nervous system tumors in children: analysis of day care, social contact, and overcrowding Cancer Causes Control 20 129 136.

    • Search Google Scholar
    • Export Citation
  • 34. AN Hata RM Breyer 2004 Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation Pharmacol Ther 103 147 166.

    • Search Google Scholar
    • Export Citation
  • 35. P Hauser G Benyó Zs Jakab 2007 Gyermekkori medulloblastoma/PNET kezelési eredményei a Semmelweis Egyetem Gyermekklinikáin Gyermekgyógyászat 58 19 25.

    • Search Google Scholar
    • Export Citation
  • 36. P Hauser Z Jakab O Láng 2005 Incidence and survival of central nervous system involvement in childhood malignancies: Hungarian experience J Pediatr Hematol Oncol 27 125 128.

    • Search Google Scholar
    • Export Citation
  • 37. P Hauser Z Jakab O Láng 2003 High incidence of brain tumors of childhood in Hungary between 1989 and 2001 Med Pediatr Oncol 41 590 591.

    • Search Google Scholar
    • Export Citation
  • 38. P Hauser Zs Jakab Cs Kiss 2009 Előzetes eredmények a medulloblastoma/primitív neuroektodermális tumor (PNET) kezelésében a magyar MBL 2004 kezelési sémával Magyar Belorvosi Archívum 62 196 201.

    • Search Google Scholar
    • Export Citation
  • 39. R Hernan R Fasheh C Calabrese 2003 ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma Cancer Res 63 140 148.

    • Search Google Scholar
    • Export Citation
  • 40. K von Hoff B Hinkes NU Gerber 2009 Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91 Eur J Cancer 45 1209 1217.

    • Search Google Scholar
    • Export Citation
  • 41. K Imai S Matsuyama S Miyake 2000 Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population Lancet 356 1795 1799.

    • Search Google Scholar
    • Export Citation
  • 42. RL Johnson AL Rothman J Xie 1996 Human homolog of patched, a candidate gene for the basal cell nevus syndrome Science 272 1668 1671.

    • Search Google Scholar
    • Export Citation
  • 43. Z Kaderali M Lamberti-Pasculli JT Rutka 2009 The changing epidemiology of paediatric brain tumours: a review from the Hospital for Sick Children Childs Nerv Syst 25 787 793.

    • Search Google Scholar
    • Export Citation
  • 44. MW Kieran CD Turner JB Rubin 2005 A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer J Pediatr Hematol Oncol 27 573 581.

    • Search Google Scholar
    • Export Citation
  • 45. K Gumireddy LN Sutton PC Phillips CE Reddy 2003 All-trans-retinoic acid-induced apoptosis in human medulloblastoma: activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway Clin Cancer Res 9 4052 4059.

    • Search Google Scholar
    • Export Citation
  • 46. RD Kortmann J Kuhl B Timmermann 2000 Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood, results of the German prospective randomized trial HIT'91 Int J Radiat Oncol Biol Phys 46 269 279.

    • Search Google Scholar
    • Export Citation
  • 47. J Liu L Guo N Liu 2000 Retinoic acid enhances chemosensitivity of medulloblastoma cells in vitro and its potential mechanism Zhonghua Zhong Liu Za Zhi 22 11 13.

    • Search Google Scholar
    • Export Citation
  • 48. J Liu L Guo Y Luo 2000 All trans-retinoic acid suppresses in vitro growth and down-regulates LIF gene expression as well as telomerase activity of human medulloblastoma cells Anticancer Res 20 2659 2664.

    • Search Google Scholar
    • Export Citation
  • 49. XN Li Q Shu JM Su 2005 Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC Mol Cancer Ther 4 1912 1922.

    • Search Google Scholar
    • Export Citation
  • 50. TJ MacDonald KM Brown B LaFleur 2001 Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease Nat Genet 29 143 152.

    • Search Google Scholar
    • Export Citation
  • 51. M Maden 2007 Retinoic acid in the development, regeneration and maintenance of the nervous system Nat Rev Neurosci 8 755 765.

  • 52. KJ Malmberg YT Bryceson M Carlsten 2008 NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy Cancer Immunol Immunother 57 1541 1552.

    • Search Google Scholar
    • Export Citation
  • 53. S Marino M Vooijs H van Der Gulden 2000 Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum Genes Dev 14 994 1004.

    • Search Google Scholar
    • Export Citation
  • 54. DE McNeil TR Coté L Clegg LB Rorke 2002 Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance Epidemiology and End Results Med Pediatr Oncol 39 190 194.

    • Search Google Scholar
    • Export Citation
  • 55. DA Mitchell PE Fecci JH Sampson 2008 Immunotherapy of malignant brain tumors Immunol Rev 222 70 100.

  • 56. RK Mulhern JL Kepner PR Thomas 1998 Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study J Clin Oncol 16 1723 1728.

    • Search Google Scholar
    • Export Citation
  • 57. Y Nakahara PA Northcott MH Li 2010 Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma Neoplasia 12 20 27.

    • Search Google Scholar
    • Export Citation
  • 58. Narayana A , Kunnakkat S, Chacko-Mathew J, et al. Bevacizumab in recurrent high-grade pediatric gliomas. Neuro Oncol, 2010, PMID: 20363768.

    • Search Google Scholar
    • Export Citation
  • 59. N Nausch A Cerwenka 2008 NKG2D ligands in tumor immunity Oncogene 27 5944 5958.

  • 60. K Paal V Erdelyi-Toth E Pap 1994 Pharmacokinetic studies on Elobromol in children with brain tumors Anticancer Drugs 5 539 547.

  • 61. RJ Packer A Gajjar G Vezina 2006 Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma J Clin Oncol 24 4202 4208.

    • Search Google Scholar
    • Export Citation
  • 62. RJ Packer LN Sutton R Eltermen 1994 Outcome of children with medulloblastoma treated with radiation, cisplatin, CCNU and vincristine chemotherapy J Neurosurg 81 690 698.

    • Search Google Scholar
    • Export Citation
  • 63. RJ Packer J Goldwein HS Nicholson 1999 Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study J Clin Oncol 17 2127 2136.

    • Search Google Scholar
    • Export Citation
  • 64. DW Parsons S Jones X Zhang 2008 An integrated genomic analysis of human glioblastoma multiforme Science 321 1807 1812.

  • 65. J Pizem A Cört L Zadravec-Zaletel M Popovic 2005 Surviving is a negative prognostic marker in medulloblastoma Neuropathol Appl Neurobiol 31 422 428.

    • Search Google Scholar
    • Export Citation
  • 66. CM Rudin CL Hann J Laterra 2009 Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449 N Engl J Med 12 1173 1178.

  • 67. S Rutkowski U Bode F Deinlein 2005 Treatment of early childhood medulloblastoma by postoperative chemotherapy alone N Engl J Med 352 978 986.

    • Search Google Scholar
    • Export Citation
  • 68. A Salmaggi A Dufour A Silvani 1994 Immunological fluctuations during intrathecal immunotherapy in three patients affected by CNS tumours disseminating via CSF Int J Neurosci 77 117 125.

    • Search Google Scholar
    • Export Citation
  • 69. D Schuler P Somlo J Borsi 1988 New drug combination for the treatment of relapsed brain tumors in children Pediatr Hematol Oncol 5 153 156.

    • Search Google Scholar
    • Export Citation
  • 70. D Schuler P Somlo R Koos 1992 Treatment of malignant scala posterior brain tumors in children: the chemotherapy of relapsed medulloblastoma with a dibromdulcitol containing drug regime and pharmacokinetic studies of dibromdulcitol in children Med Pediatr Oncol 20 312 314.

    • Search Google Scholar
    • Export Citation
  • 71. D Schuler P Somlo R Koos 1993 The treatment of malignant scala posterior tumors in children: II. Preliminary result of the pre- and postoperative adjuvant chemotherapy of scala posterior tumors Med Pediatr Oncol 21 274 279.

    • Search Google Scholar
    • Export Citation
  • 72. J Schüz P Kaatsch 2002 Epidemiology of pediatric tumors of the central nervous system Exp Rev Neurother 2 469 479.

  • 73. K Shimizu K Tamura M Yamada 1989 Adoptive immunotherapy in patients with medulloblastoma by LAK cells No To Shinkei 41 991 995.

  • 74. Q Shu B Antalffy JM Su 2006 Valproic acid prolongs survival time of severe combined immunodeficient mice bearing intracerebellar orthotopic medulloblastoma xenografts Clin Cancer Res 12 4687 4694.

    • Search Google Scholar
    • Export Citation
  • 75. A Silvani A Salmaggi G Parmiani A Boiardi 1994 Successful adoptive immunotherapy with lymphokine-activated killer cells in the treatment of medulloblastoma disseminated via cerebrospinal fluid: case report Neurosurgery 34 1078 1080.

    • Search Google Scholar
    • Export Citation
  • 76. ML Slongo B Molena AM Brunati 2007 Functional VEGF and VEGF receptors are expressed in human medulloblastomas Neuro Oncol 9 384 392.

    • Search Google Scholar
    • Export Citation
  • 77. S Staal MJ O'Connell CJ Allegra 2009 The marriage of growth factor inhibitors and chemotherapy: bliss or bust? J Clin Oncol 27 1545 1548.

    • Search Google Scholar
    • Export Citation
  • 78. A Stevens I Klöter W Roggendorf 1988 Inflammatory infiltrates and natural killer cell presence in human brain tumors Cancer 61 738 743.

    • Search Google Scholar
    • Export Citation
  • 79. KW Sung KH Yoo EJ Cho 2007 High-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor Pediatr Blood Cancer 48 408 415.

    • Search Google Scholar
    • Export Citation
  • 80. H Takei Y Nguyen V Mehta 2009 Low-level copy gain versus amplification of myc oncogenes in medulloblastoma: utility in predicting prognosis and survival. Laboratory investigation J Neurosurg Pediatr 3 61 65.

    • Search Google Scholar
    • Export Citation
  • 81. E Taniguchi MJ Cho BR Arenkiel 2009 Bortezomib reverses a post-translational mechanism of tumorigenesis for patched1 haploinsufficiency in medulloblastoma Pediatr Blood Cancer 53 136 144.

    • Search Google Scholar
    • Export Citation
  • 82. RE Taylor CC Bailey K Robinson International Society of Paediatric Oncology; United Kingdom Children's Cancer Study Group 2003 Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study J Clin Oncol 21 1581 1591.

    • Search Google Scholar
    • Export Citation
  • 83. MC Thompson C Fuller TL Hogg 2006 Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations J Clin Oncol 24 1924 1931.

    • Search Google Scholar
    • Export Citation
  • 84. L Wang W Chen X Xie 2008 Celecoxib inhibits tumor growth and angiogenesis in an orthotopic implantation tumor model of human colon cancer Exp Oncol 30 42 51.

    • Search Google Scholar
    • Export Citation
  • 85. XF Xu CG Xie XP Wang 2008 Selective inhibition of cyclooxygenase-2 suppresses the growth of pancreatic cancer cells in vitro and in vivo Tohoku J Exp Med 215 149 157.

    • Search Google Scholar
    • Export Citation