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Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) The pivotal role of CTP synthetase in the metabolism of (deoxy)nucleosides in neuroblastoma Bierau, J. Publication date 2003 Link to publication Citation for published version (APA): Bierau, J. (2003). The pivotal role of CTP synthetase in the metabolism of (deoxy)nucleosides in neuroblastoma. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:27 Sep 2021 1 1 Introduction n "Nucleotidess are water-soluble components which naturally occur, inn larger or smaller portions, in both animal and vegetable foods. Combinedd with other components, theyy are the elements to bring the flavor in food." fromm the Ajinomoto Europe website ChapterChapter 1 Introduction n 1.11 General introduction to neuroblastoma Incidence Incidence Neuroblastomaa is the most common extra cranial solid cancer of childhood. It is the most frequentlyy occurring form of cancer in children after brain tumours, acute lymphatic leukaemiaa (ALL) and lymphoma. About 7% of all malignancies in children under 15 years of agee are neuroblastomas. The reported incidence of neuroblastoma varies between 9 and 35 per millionn children, with slight variations between different parts of the world. Boys appear to havee a 1.2-fold higher risk of developing neuroblastoma compared to girls (National Cancer Institute,, 2002;Brodeur and Castleberry, 1997). Symptoms Symptoms Neuroblastomaa is a tumour of the neural crest and originates in the adrenal medulla or the paraspinall sites where sympathetic nervous tissue is present. The most common symptoms aree a large tumour mass or pain in the bones caused by metastasis. Other common symptoms aree bulging eyes (proptosis) and bruises around the eye (periorbital ecchymosis) and are causedd by retrobulbar metastasis. Neuroblastomas can invade through the neural foramina and causee paralysis by compressing the spinal cord. Other, less frequently occurring symptoms includee fever, anaemia, hypertension, diarrhoea, cerebellar ataxia, opsoclonus and myoclonus (Nationall Cancer Institute, 2002;Azizkhan and Haase, 1993;Connolly et al, 1997;Rudnick et al,al, 2001). Diagnosis Diagnosis Besidee the brain, cells derived from the neural crest are the primary source of neurotransmitters,, such as dopamine, epinephrine and norepinephrine in the body. These catecholaminess are synthesised from L-3,4-dihydroxyphenylalanine (L-DOPA), which in turn iss synthesised from tyrosine. Normal, mature neural crest-derived cells store their neurotransmiterss in secretory vessicles until release. After excretion, neurotransmitters exert theirr activity on other cells that are sensitive to neurotransmitters. The neurotransmitters are deactivedd by presynaptic uptake, conjugation to sulphate or glucoronic acid and finally by excretionn in the urine. In patients suffering from neuroblastoma, an increased production and subsequentt secretion of catecholamines in urine is observed. Determination of metabolites of L-DOPAA in urine is routinely used in the diagnosis of neuroblastoma. Thee biosynthesis and degradation of the metabolites of L-DOPA is catalysed by a large numberr of enzymes. In mature, differentiated, neuronal cells, all the enzymes of the catecholaminee metabolic pathway are expressed and thus the end-products of this pathway are synthesised.. In less differentiated cells, such as neuroblastoma cells, not all enzymes involved inn catacholamine biosynthesis are expressed. Undifferentiated neuroblastoma cells synthesise ann increased amount of dopamine and DOPA (early metabolites in the DOPA-metabolism) comparedd to norepinephrine. The pattern of the degradation metabolites of L-DOPA in urine usuallyy reflects the relative activities of the enzymes involved in the metabolism of L-DOPA. Thus,, the pattern of L-DOPA metabolites excreted in urine serves as a marker for the detectionn of neuroblastoma and in addition provides information on the degree of differentiationn of the tumour (Abeling et al, 1986). Alternatively,, neuroblastomas can also be detected by using [131I] or [125I] radio-labelled meta-iodobenzylguanidinee (MIBG). MIBG is a structural analogue of the neurotransmitter norepinephrine.. MIBG is recognised by the norepinephrine transport protein and accumulates inn neurendrocrine tissue after its administration to the patient (Wieland et al, 1980). 10 0 Introduction Introduction Neuroblastomaa cells abundantly express the norepinephrine transport protein, and therefore accumulatee the radio-labelled MIBG thus allowing the detection of the neuroblastoma by scintigraphy.. In rare cases, neuroblastoma can be discovered prenatally by foetal ultrasonographyy (National Cancer Institute, 2002) (Jennings et al, 1993). INTERNATIONALL NEUROBLASTOMA STAGING SYSTEM (INSS) INSSS Stage Description n Stagee 1 Localisedd tumour with complete gross excision, with or without microscopicc residual disease. Representative ipsilateral lymph nodes negativee for tumour microscopically (nodes attached to and removed with thee primary tumour may be positive, (ipsilateral: situated or appearing on or affectingg the same side of the body Stagee 2A Localisedd tumour with incomplete gross excision. Representative ipsilateral non-adherentt lymph nodes negative for tumour microscopically. Stagee 2B Localisedd tumour with or without complete gross excision, with ipsilateral nonadherentt lymph nodes positive for tumour. Enlarged contralateral lymphh nodes must be negative microscopically, (contralateral: occurring on orr acting in conjunction with a part on the opposite side of the body Stagee 3 Unresectablee unilateral tumour infiltrating across the midline, with or withoutt regional lymph node involvement; localised unilateral tumour with contralaterall regional lymph node involvement; midline tumour with bilaterall extension by infiltration (unresectable) or by lymph node involvement.. The midline is defined as the vertebral column. Tumours originatingg on one side and crossing the midline must infiltrate to or beyondd the opposite side of the vertebral column. Stagee 4 Anyy primary tumour with dissemination to distant lymph nodes, bone, bone marrow,, liver, skin and/or other organs (except as defined for stage 4S). Stagee 4S Localisedd primary tumour (as defined for stage 1, 2A, or 2B), with disseminationn limited to skin, liver, and/or bone marrow (limited to infants lesss than 1 year age). Marrow involvement should be minimal (i.e. < 10% off total nucleated cells identified as malignant by bone biopsy or by bone marroww aspirate). More extensive bone marrow involvement would be consideredd to be stage 4 disease. The results of a MIBG scan should be negativee for disease in the bone marrow. Tablee 1: International Neuroblastoma Staging System (Brodeur et al, 1993;Brodeur et al, 1988;Castleberryy et al, 1997) 11 1 ChapterChapter 1 StagingStaging and prognosis Thee prognosis for children suffering from neuroblastoma is highly dependent on the age at diagnosiss and on the stage of the disease. The disease is characterised by 5 distinct prognostic stages.. The staging of the disease according to the International Neuroblastoma Staging Systemm (INSS) is outlined in table 1. Approximately 75 % of the children with neuroblastomaa have metastasised disease at the time of diagnosis. About 20 % of the children withh neuroblastoma have stage I or II disease. Regardless of age, these children with stage I or III disease have a cure rate of over 90 %. Approximately 20 % of the children suffering from neuroblastomaneuroblastoma present with stage III disease and 55 % present with stage IV disease. The prognosiss for patients with stage III/IV disease is poor with a survival rate of 10-25 %, but stronglyy depends on the age of the patient. Children younger than 1 year of age, with favourablee disease characteristics at diagnosis, have a 50-80% chance of 5-year event free survival,, regardless of the stage of the disease. The long-term survival of children older than onee year of age ranges from 10-40%. Stage IVs neuroblastomas comprise approximately 5 % off all neuroblastomas and present mostly in very young infants. These tumours have a high ratee of spontaneous regression and the 5-year survival is greater than 90% (Cotterill et al, 2000;Nationall Cancer Institute, 2002). 1.22 Genetic prognostic markers Thee clinical diversity of neuroblastoma correlates with several characteristic molecular biologicall features observed in neuroblastoma. The most significant progonostic factors are amplificationn of the MYCN oncogene, tumour cell ploidy, deletions of the short arm of chromosomee 1 and gain of chromosome 17q. Amplificationn of the MYCN oncogene has been demonstrated in about 25% of
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