Changes of amino acid serum levels in pediatric patients with higher-risk acute lymphoblastic leukemia (CCG-1961).
BACKGROUND
Deamination of asparagine (Asn) and glutamine (Gln) by asparaginases (ASNase) is associated with good prognosis in acute lymphoblastic leukemia (ALL). Chemotherapy drugs used for ALL may accelerate catabolism of other amino acids (AA).


METHODS
We studied ASNase activity and changes of Asn, Gln, serine (Ser), threonine (Thr), histidine (His), proline (Pro) and arginine (Arg) levels and sought relationships in sera from 73 pediatric ALL patients, who received ASNase-containing chemotherapy.


RESULTS
Asparaginase activity averaged 0.4+/-0.34 IU/ml (mean+/-SDEV) in all specimens. All AA decreased after treatment, ranging from 18.6%-82.6% of control. Asparaginase activity of 0.7 IU/ml provided 90% Asn and Gl deamination. The data were dichotomized in subsets of low ASNase (range 0.02-0.39 IU/ml, mean=0.17+/-0.09 IU/ml) and high ASNase (range 0.4-1.69 IU/ml and mean=0.72+/-0.32 IU/ml). Asparagine and Gln % deamination values were correlated with ASNase activity (p=0.0002 and p=0.0001). Similarly, decreases of Arg and Ser levels were also correlated, p =0.0009 and p=0.032, respectively. In the high ASNase subset, a 39% decrease of Arg and 26% of Ser was obtained. Low ASNase activity was correlated with lower Asn and Gln % deamination and with moderate decrease of Ser (14.6%) and Arg (19.6%). Threonine, Pro and His also decreased, but no correlations were obtained with ASNase activity.


CONCLUSIONS
Asparagine, Gln and five other AA declined during ASNase treatment. Asparagine and Gln % deamination values are highly correlated with serum ASNase activity. Asparaginase may indirectly cause moderate depletion of serum Arg and Ser levels, providing an enhancement in leukemia blasts apoptosis. Toxicity from the ASNase and other drugs could enhance the decrease of AA serum levels. Further studies are needed to verify these findings and their potential clinical importance in the treatment of ALL patients.
Grigoryan
Rita S
RS
Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Panosyan
Eduard H
EH
Seibel
Nita L
NL
Gaynon
Paul S
PS
Avramis
Ioannis A
IA
Avramis
Vassilios I
VI
D000596:Amino Acids / Q000097:blood*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001215:Asparaginase / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood; D002648:Child; D002952:Citric Acid Cycle / Q000187:drug effects / Q000502:physiology; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology*
D000596:Amino Acids; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001215:Asparaginase