Approaches to Treatment of Children with Advanced Neuroblastoma

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Children with advanced neuroblastoma are at high risk for relapse of multidrug resistant disease, despite initial response to intensive multimodality treatment. Neuroblastomas have similarities with immature neuroblasts seen during embryonic development of the sympathetic nervous system (the origin of these tumors). Chemotherapeutic drugs have various mechanisms of action and successfully treated cancer cells eventually undergo programmed cell death (apoptosis). Hence, impaired apoptotic pathways can be one explanation for drug resistance, but also represent causes for tumor initiation, progression and metastatic spread. Tumor hypoxia (low oxygen levels) due to rapid cell overgrowth and impaired vascularization is another obstacle in cancer treatment, especially recognized by radiotherapists. Recent studies have revealed that tumor hypoxia affect malignant potential of tumor cells through increased genomic instability and metastatic ability.

We have identified that the embryonic transcription factor dHAND is exclusively expressed in neuroblastomas, and this protein/gene might represent a potential diagnostic marker and target for future therapy. In addition, we have found that hypoxia alters neuroblastoma cells toward an immature phenotype and we hypothesize that hypoxic cells de-differentiate and thereby retain their migration capacities, which could be an explanation for tumor progression. Hypoxic neuroblastoma cells were found resistant to cytotoxic drugs but not to mitomycin C, and we propose that this compound might be useful for targeting the hypoxic cells in the initial treatment of neuroblastoma. Arsenic trioxide, a newly re-introduced drug in the treatment of relapsed and drug-resistant acute promyelocytic leukemia, induces a p53-independent apoptotic cell death in neuroblastoma cells, which is in contrast to conventional cytotoxic agents. We suggest that arsenic trioxide could be useful in the clinical setting in the treatment of children with advanced neuroblastoma.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Paediatrics (Lund)
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date2003 Feb 12
Publisher
Print ISBNs91-628-5541-7
Publication statusPublished - 2003

Bibliographical note

Defence details

Date: 2003-02-12
Time: 10:15
Place: Lecture Hall 1, University Hospital Lund

External reviewer(s)

Name: Pearson, Andrew D. J.
Title: Professor
Affiliation: Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

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Article: I. Gestblom C, Grynfeld A, Øra I, Örtoft E, Larsson C, Axelson H, Sandstedt B, Cserjesi P, Olson EN, and Påhlman S. The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high and low stage neuroblastomas. Lab Invest 79:67-79, 1999.

Article: II. Jögi A, Øra I, Nilsson H, Lindeheim Å, Makino Y, Poellinger L, Axelson H, and Påhlman S. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci USA 99:7021-7026, 2002.

Article: III. Øra I, Bondesson L, Ljungberg J, Jönsson C, Lindeheim Å, Pörn-Ares I, Garwicz S, and Påhlman S. Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro. Biochem Biophys Res Commun 277:179-185, 2000.

Article: IV. Karlsson J, Øra I, Pörn-Ares I, and Påhlman S. Arsenic trioxide-induced death of neuroblastoma cells involves activation of Bax and release of cytochrome C, and does not require p53 and caspase activity. Submitted, 2002.V. Øra I, Garwicz S, and Påhlman S. Low oxygen levels affect cytotoxicity of arsenic trioxide and conventional cytostatic drugs in neuroblastoma cells. Manuscript, 2002.

Subject classification (UKÄ)

  • Pediatrics

Keywords

  • Pediatrics
  • drug resistance
  • hypoxia
  • apoptosis
  • arsenic trioxide
  • treatment
  • diagnosis
  • neuroblastoma
  • sympathetic nervous system
  • Pediatri
  • Cytology
  • oncology
  • cancerology
  • Cytologi
  • onkologi
  • cancer

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