TY - JOUR
T1 - Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia
AU - Appel, Inge M
AU - den Boer, Monique L
AU - Meijerink, Jules P P
AU - Veerman, Anjo J P
AU - Reniers, Nathalie C M
AU - Pieters, Rob
PY - 2006/6/1
Y1 - 2006/6/1
N2 - L-asparaginase (L-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of L-Asp by resynthesis of asparagine. In vitro, resistance to L-Asp has been associated with up-regulation of AS mRNA expression. We monitored AS mRNA levels in leukemic cells before and during 5 days after intravenous administration of 1000 IU/m(2) pegylated L-asparaginase (PEG-Asp) in a therapeutic window in children with ALL at initial diagnosis. Within 24 hours, AS mRNA levels increased by 3.5-fold and remained stable in the following 4 days. Baseline and L-Asp-induced expression levels of AS did not differ between clinically good, intermediate, and poor responders to PEG-Asp. No significant difference of AS mRNA up-regulation was found between precursor B- and T-ALL or between hyperdiploids, TEL/AML1 rearranged ALL or absence of genetic abnormalities. In 3 of 12 patients with T-ALL even a slight down-regulation of AS mRNA expression upon L-Asp exposure was found. In conclusion, although L-Asp exposure induces the expression of AS mRNA, the up-regulated gene expression does not correlate with an early clinical poor response to this drug in children with ALL.
AB - L-asparaginase (L-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of L-Asp by resynthesis of asparagine. In vitro, resistance to L-Asp has been associated with up-regulation of AS mRNA expression. We monitored AS mRNA levels in leukemic cells before and during 5 days after intravenous administration of 1000 IU/m(2) pegylated L-asparaginase (PEG-Asp) in a therapeutic window in children with ALL at initial diagnosis. Within 24 hours, AS mRNA levels increased by 3.5-fold and remained stable in the following 4 days. Baseline and L-Asp-induced expression levels of AS did not differ between clinically good, intermediate, and poor responders to PEG-Asp. No significant difference of AS mRNA up-regulation was found between precursor B- and T-ALL or between hyperdiploids, TEL/AML1 rearranged ALL or absence of genetic abnormalities. In 3 of 12 patients with T-ALL even a slight down-regulation of AS mRNA expression upon L-Asp exposure was found. In conclusion, although L-Asp exposure induces the expression of AS mRNA, the up-regulated gene expression does not correlate with an early clinical poor response to this drug in children with ALL.
KW - Adolescent
KW - Antineoplastic Agents/pharmacology
KW - Asparaginase/pharmacology
KW - Aspartate-Ammonia Ligase/genetics
KW - Child
KW - Child, Preschool
KW - Female
KW - Humans
KW - Infant
KW - Leukemia-Lymphoma, Adult T-Cell/drug therapy
KW - Male
KW - Polyethylene Glycols/pharmacology
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - RNA, Neoplasm/analysis
KW - Treatment Outcome
KW - Up-Regulation/drug effects
U2 - 10.1182/blood-2005-06-2597
DO - 10.1182/blood-2005-06-2597
M3 - Article
C2 - 16497975
SN - 0006-4971
VL - 107
SP - 4244
EP - 4249
JO - Blood
JF - Blood
IS - 11
ER -