The p53 pathway and its inactivation in neuroblastoma Deborah A. Tweddle a,b, * , Andrew D.J. Pearson b , Michelle Haber c , Murray D. Norris c , Chengyuan Xue c , Claudia Flemming c , John Lunec a a Cancer Research Unit, The Medical School, University of Newcastle, Newcastle-upon-Tyne, NE2 4HH, UK b Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle-upon-Tyne, NE1 4LP, UK c Children’s Cancer Institute Australia for Medical Research, P.O. Box 81 (High Street), Randwick, Sydney, NSW, Australia 2031 Received 4 November 2002; accepted 11 November 2002 Abstract Early studies of p53 in neuroblastoma reported infrequent mutations in tumours and cell lines. Cytoplasmic sequestration was later proposed as an alternative mechanism of inactivation, but many studies have since reported an intact p53 pathway in neuroblastoma cell lines, as detected by nuclear p53 accumulation after DNA damage, intact DNA binding, transcriptional activation of target genes and the induction of apoptosis. In some MYCN amplified cell lines however, an irradiation induced G 1 arrest does not occur, despite the presence of normal p53. Neuroblastoma usually responds to chemotherapy but frequently relapses, and there is evidence from tumours, and cell lines that p53 inactivation via mutation or MDM2amplification occurs at relapse and is sometimes associated with multidrug resistance. If p53 inactivation occurs frequently in relapsed tumours it may be appropriate to include p53 independent therapies in the initial management of high-risk neuroblastoma. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Neuroblastoma; p53; Mutation; MYCN; MDM2; Drug resistance; Therapy; Survival; Cytotoxic; Relapse 1. Introduction Unlike the improvements in survival in many childhood cancers, high-risk neuroblastoma is still one of the most difficult tumours to cure, with only 30% long-term survival despite intensive multi-modal therapy. New treatments and a better understanding of drug resistance mechanisms are required before the survival rates can significantly improve. An important mechanism of resistance to cytotoxic therapy in many tumour cells is an abnormality in the p53 tumour suppressor gene pathway [1]. The subject of p53 inactivation in neuroblastoma has been one of the most controversial areas in neuroblastoma research to date. This review draws together the apparently conflicting data and concludes that knowl- edge of p53 function in neuroblastoma may help in planning appropriate therapy in the future. 2. The p53 pathway The nuclear phosphoprotein, p53, is usually present at low levels in the cell, due to a short half- 0304-3835/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3835(03)00088-0 Cancer Letters 197 (2003) 93–98 www.elsevier.com/locate/canlet * Corresponding author. Cancer Research Unit, The Medical School, University of Newcastle, Framlington Place, NE2 4HH, UK. Tel.: þ44-191-222-8221; fax: þ 44-191-222-7556. E-mail address: d.a.tweddle@newcastle.ac.uk (D.A. Tweddle).