Abstract
Background and Objectives: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood. The majority of patients respond to treatment, but those with resistant phenotypes suffer relapse or death. The antifolate methotrexate (MTX) is the most commonly used drug against ALL due to its efficacy. Once inside leukemic cells, MTX is metabolized into methotrexate polyglutamates (MTX-PG) by action of the enzyme folylpolyglutamate synthetase (FPGS), leading to a longer action compared to that of MTX alone. Materials and Methods: In this work, we demonstrated that the combination treatment of methotrexate and 5 and 10 mM glutamic acid could enhance methotrexate cytotoxicity in CCRF-SB (B-ALL) cells. In addition, MTX plus 20 mM glutamic acid was able to improve the synthesis of MTX-PG5. Results: All treatments induced an increase in FPGS expression compared to that of the control group. Furthermore, we detected different cellular expression patterns of FPGS in the different treatments. Conclusion: Based on these findings, we demonstrated that levels of methotrexate polyglutamates (MTX-PGs) could be a key determinant of methotrexate-induced cytotoxicity in CCRF-SB acute lymphoblastic leukemia cells.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood, with an incidence peak between 2 and 5 years of age [1]
To evaluate the pharmacological effect resulting from the combination of glutamic acid and MTX, we determined the intracellular accumulation of methotrexate polyglutamates (MTX-PG) in the ALL cell line after simultaneous treatment with both drugs
Data from the present study indicate that co-treatment with glutamic acid (Glu) at concentrations of 10 and 20 mM plus the highly effective antileukemic drug MTX improves the cytotoxicity of MTX and promotes an increase in the synthesis of MTX-PGs in CCRF-SB (B-ALL)
Summary
Acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood, with an incidence peak between 2 and 5 years of age [1]. The majority of patients with ALL respond well to therapy, a poor outcome remains for patients with resistant phenotypes as well as for those who suffer a relapse [2]. For this reason, novel strategies for the treatment of childhood ALL are needed to improve the effectiveness of the current chemotherapeutic drugs and increase the cure rate and reduce toxicity to non-malignant cells.
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