Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961).
BACKGROUND
Glutamine (Gln) deamination by asparaginase (ASNase) appears to contribute in the decrease of serum asparagine (Asn) levels and enhance leukemic cell apoptosis. The pharmacodynamic (PD) rationale is based on the role of Gln as the main amino group donor for Asn synthesis from aspartate by the enzyme asparagine synthetase (AS).


METHODS
Relationships between ASNase enzymatic activity and Asn or Gln levels were examined in 274 pairs of pre- and post-ASNase serum specimens from 200 high-risk acute lymphoblastic leukemia (ALL) patients from the Children's Cancer Group (CCG-1961). Data were analyzed according to a novel PD model based on previous best-fit projections (NONMEM) from the CCG-1962 standard-risk ALL study.


RESULTS
The PD results from high-risk and standard-risk ALL patients were superimposable. The percentages of Asn and Gln deamination were predicted by ASNase activity in patients' sera. Pharmacodynamic analyses strongly suggested that > 90% deamination of Gln must occur before optimal Asn deamination takes place in vivo. Asparaginase activity > or = 0.4 IU/ml yielded mean Gln and Asn % deamination values of 90%. Lower ASNase concentrations yielded lower Gln or Asn % deamination. This ASNase concentration coincides with the in vitro determined IC50 value on CEM/0 human T-lymphoblastic leukemia cells.


CONCLUSIONS
Asparaginase activity of > or = 0.4 IU/ml provided optimal Asn and Gln deamination in high-risk ALL patients. Deamination of Gln correlates with enhanced serum Asn deamination in vivo. Therefore, deamination of Gln may enhance the antileukemic effect of ASNase.
Panosyan
Eduard H
EH
Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Grigoryan
Rita S
RS
Avramis
Ioannis A
IA
Seibel
Nita L
NL
Gaynon
Paul S
PS
Siegel
Stuart E
SE
Fingert
Howard J
HJ
Avramis
Vassilios I
VI
D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D001215:Asparaginase / Q000097:blood / Q000494:pharmacology*; D001216:Asparagine / Q000097:blood*; D003641:Deamination; D005973:Glutamine / Q000097:blood*; D006801:Humans; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
D000970:Antineoplastic Agents; D005973:Glutamine; D001216:Asparagine; D001215:Asparaginase