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In vitro activity of the novel cytotoxic agent CHS 828 in childhood acute leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Cancer Pharmacology and Informatic)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer Pharmacology and Informatics)
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2002 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 13, no 7, 735-742 p.Article in journal (Refereed) Published
Abstract [en]

CHS 828, a pyridyl cyanoguanidine, is a new drug candidate now in phase I/II trials, that has shown promising anticancer activity in experimental tumor models and primary cultures of cancer cells from patients. In this study the fluorometric microculture cytotoxicity assay was used for evaluation of CHS 828 in primary cell cultures from children with acute leukemia. The activity of and interaction with the standard drugs, doxorubicin, melphalan, etoposide and cytosine arabinoside (Ara-C), were also assessed. Samples from 65 patients, 42 with acute lymphocytic leukemia (ALL) and 23 with acute myelocytic leukemia (AML) were tested with 72-h continuous drug exposure. There was 50% cell kill at very low CHS 828 concentrations; median IC50 was 0.01 microM in ALL and 0.03 in AML samples (NS) with large interindividual variability in both groups. ALL samples were significantly more sensitive than AML samples to melphalan, doxorubicin and etoposide, but not to Ara-C. In AML samples, combinations between CHS 828 and each of the four standard drugs resulted in significantly lower cell survival than either drug alone. This was also observed in ALL samples, except for Ara-C. Using the additive interaction model, CHS 828 showed a synergistic effect with melphalan in 67%, doxorubicin in 47%, etoposide in 38% and Ara-C in 14% of AML samples. In most ALL samples subadditive effects were found. Further exploration of CHS 828 in childhood leukemia is warranted, especially in AML.

Place, publisher, year, edition, pages
2002. Vol. 13, no 7, 735-742 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89995PubMedID: 12187330OAI: oai:DiVA.org:uu-89995DiVA: diva2:161993
Available from: 2002-10-10 Created: 2002-10-10 Last updated: 2017-12-14Bibliographically 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.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1189
Keyword
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
Pediatrics
Identifiers
urn:nbn:se:uu:diva-2664 (URN)91-554-5417-8 (ISBN)
Public defence
2002-11-01, Rosén salen, Uppsala, 09:15
Opponent
Available from: 2002-10-10 Created: 2002-10-10Bibliographically approved

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Frost, Britt-MarieLönnerholm, GudmarNygren, PeterLarsson, RolfLindhagen, Elin

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