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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2879-2886
NEOPLASIA
Cellular drug resistance profiles in childhood acute myeloid
leukemia: differences between FAB types and comparison with acute
lymphoblastic leukemia
Christian M. Zwaan,
Gert-Jan L. Kaspers,
Rob Pieters,
Nicole L. Ramakers-Van Woerden,
Monique L. den Boer,
Renate Wünsche,
Maria M. A. Rottier,
Karel Hählen,
Elizabeth R. van
Wering,
Gritta E. Janka-Schaub,
Ursula Creutzig, and
Anjo J. P. Veerman
From the Department of Pediatric Hematology/Oncology,
University Hospital Vrije Universiteit, Amsterdam, The Netherlands; the
Department of Oncology/Hematology, Sophia Children's Hospital and
University Hospital Rotterdam, Rotterdam, The Netherlands; the Dutch
Childhood Leukemia Study Group, Den Haag, The Netherlands; the
Cooperative ALL Study Group, University Hospital Eppendorf,
Hamburg, Germany; and the AML-Berlin-Frankfurt-Münster Study
Group, University Children's Hospital Münster, Münster,
Germany.
Determining in vitro drug resistance may reveal clinically relevant
information in childhood leukemia. Using the
methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic
cells to 21 drugs was compared in 128 children with acute myeloid
leukemia (AML) and 536 children with acute lymphoblastic leukemia
(ALL). The differences between 3 French-American-British (FAB) types
(M1/M2, M4, and M5) were also compared. AML was significantly more
resistant than ALL to the following drugs, as noted by the median
resistance: glucocorticoids (greater than 85-fold), vincristine
(4.4-fold), L-asparaginase (6.9-fold), anthracyclines (1.8- to 3.4-fold), mitoxantrone (2.6-fold), etoposide (4.9-fold), platinum
analogues (2.4- to 3.4-fold), ifosfamide (3.5-fold), and thiotepa
(3.9-fold). For cytarabine and thiopurines, the median LC50
values (the drug concentration that kills 5% of the cells) were equal.
Also, busulfan, amsacrine, teniposide, and vindesine showed no
significant differences, but the numbers were smaller, and the median
LC50 values were 1.3- to 5.2-fold higher in AML. None of the drugs
demonstrated greater cytotoxicity in AML. FAB M5 was significantly more
sensitive than FAB M4 to most drugs frequently used in AML, as
indicated by the following ratios of median sensitivities: the
anthracyclines (2.6- to 3.2-fold), mitoxantrone (12.5-fold), etoposide
(8.7-fold), and cytarabine (2.9-fold). For etoposide and cytarabine
(5.4- and 3.4-fold, respectively) FAB M5 was also significantly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to
L-asparaginase and vincristine as ALL. Only 15% of the AML
samples were "intermediately" sensitive to glucocorticoids, mainly
in FAB M1/M2. The poorer prognosis of childhood AML is related to
resistance to a large number of drugs. Within AML, FAB M5 had a
distinct resistance pattern. These resistance profiles may be helpful
in the rational design of further treatment protocols.
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