Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia.
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.
Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
Inge M
IM
Appel
Monique L
ML
den Boer
Jules P P
JP
Meijerink
Anjo J P
AJ
Veerman
Nathalie C M
NC
Reniers
Rob
R
Pieters
D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001215:Asparaginase / Q000494:pharmacology* / Q000627:therapeutic use; D001217:Aspartate-Ammonia Ligase / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology; D008297:Male; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D012334:RNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects*
D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase