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Cellular cytotoxic drug sensitivity in children with acute leukemia and Down's syndrome: an explanation to differences in clinical outcome?
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
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2000 In: Leukemia, Vol. 14, no 4, 943-4. p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 14, no 4, 943-4. p.
URN: urn:nbn:se:uu:diva-89994OAI: oai:DiVA.org:uu-89994DiVA: diva2:161992
Available from: 2002-10-10 Created: 2002-10-10Bibliographically approved
In thesis
1. Chemotherapy in Childhood Acute Lymphoblastic Leukemia: In vitro cellular drug resistance and pharmacokinetics
Open this publication in new window or tab >>Chemotherapy in Childhood Acute Lymphoblastic Leukemia: In vitro cellular drug resistance and pharmacokinetics
2002 (Swedish)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL).

Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up.

The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level.

Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and >6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters.

In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 85 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1189
Obstetrics and gynaecology, cytotoxicity, drug resistance, pharmacokinetics, Acute lymphoblastic leukemia, childhood, in vitro assay, vincristine, doxorubicin, Down`s syndrome, CHS 828., Obstetrik och kvinnosjukdomar
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
urn:nbn:se:uu:diva-2664 (URN)91-554-5417-8 (ISBN)
Public defence
2002-11-01, Rosén salen, Uppsala, 09:15
Available from: 2002-10-10 Created: 2002-10-10Bibliographically approved

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