Appel Inge M, den Boer Monique L, Meijerink Jules P P, Veerman Anjo J P, Reniers Nathalie C M, Pieters Rob
Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
Blood. 2006 Jun 1;107(11):4244-9. doi: 10.1182/blood-2005-06-2597. Epub 2006 Feb 23.
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.
L-天冬酰胺酶（L-Asp）是治疗儿童急性淋巴细胞白血病（ALL）的一种有效药物。其有效性一般被认为是由于血清和细胞中天冬酰胺的快速消耗所致。天冬酰胺合成酶（AS）通过天冬酰胺的再合成来对抗L-Asp的作用。在体外，对L-Asp的耐药性与AS mRNA表达上调有关。我们在初诊的ALL儿童治疗窗内静脉注射1000 IU/m²聚乙二醇化天冬酰胺酶（PEG-Asp）之前及之后的5天内，监测白血病细胞中的AS mRNA水平。在24小时内，AS mRNA水平增加了3.5倍，并在接下来的4天内保持稳定。PEG-Asp临床疗效好、中等和差的反应者之间，AS的基线水平和L-Asp诱导的表达水平没有差异。在前体B-ALL和T-ALL之间，或在超二倍体、TEL/AML1重排的ALL或无基因异常之间，未发现AS mRNA上调有显著差异。在12例T-ALL患者中有3例甚至发现L-Asp暴露后AS mRNA表达有轻微下调。总之，虽然L-Asp暴露可诱导AS mRNA表达，但上调的基因表达与ALL儿童对该药物早期临床疗效差无关。
