[Relationship between the expression of the genes encoding the key enzymes for cytarabine metabolism and the pharmacokinetics of cytarabine in the treatment of childhood acute leukemia with high-dose cytarabine].
OBJECTIVE
It has been reported that high-dose cytarabine (HD-AraC) was very effective for childhood hematological malignancies, especially for improving the long-term survival of high-risk acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and T-cell lymphoid malignancies (T-ALL, T-cell non-Hodgkin's lymphoma). This study aimed to evaluate the pharmacokinetics of HD-AraC for childhood hematological malignancies, and the relationship between the expression of the genes coding the key enzymes for Ara-C metabolism with the outcome of the patients.


METHODS
The drug levels of Ara-C in plasma and cerebrospinal fluid were detected with HPLC while HD-AraC was used, the expression of deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA in human leukemia cell lines and the bone marrow cells were investigated in 48 cases of childhood hematological malignancies with RT-PCR methods, and the relationship between the expression of these enzymes mRNA and the outcome of the patients was analyzed.


RESULTS
(1) When HD-AraC was used, the plasma levels of Ara-C and Ara-U could be respectively about 50 times and 25 times higher than those obtained when the patients were treated with regular dose of Ara-C treatment, and the level of Ara-C in cerebrospinal fluid could reach about 10% of plasma level of Ara-C. (2) There were significantly different expressions of dCK mRNA in different childhood acute leukemia (AL) patients, which were markedly related to the chemotherapy results. The expression of dCK in ALL was much higher than that in AML and relapsed AL cases. There were no significant differences in expressions of dCK in T-ALL and B lineage ALL. (3) In vitro study found that the expressions of dCK and CDA mRNA did not change in leukemia cell lines incubated at different doses and times of Ara-C.


CONCLUSIONS
HD-AraC was a very effective protocol for childhood hematological malignancies for it could significantly elevate the plasma and cerebrospinal fluid drug levels. The expression of dCK may be an important factor in predicting the long-term outcomes of children with hematological malignancies. Good long-term outcomes of the childhood T-ALL could be achieved as the B lineage ALL had been treated with HD-AraC regimen. As the expression levels of dCK were much lower, it may be necessary for the treatment of AML with HD-AraC for consecutive three days.
Xie
Xiao-tian
XT
Department of Pediatric Hematology/Oncology, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, China.
Jiang
Sha-yi
SY
Li
Ben-shang
BS
Yang
Li-li
LL
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D002648:Child; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000235:genetics; D003842:Deoxycytidine Kinase / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase