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Antiproliferative effects of L-asparaginase in acute myeloid leukemia.

ABSTRACT: The antitumor enzyme L-asparaginase (L-Asp) has commonly been used for the treatment of acute lymphoblastic leukemia. However, the effects of L-Asp on acute myeloid leukemia (AML) and their underlying mechanisms have not been fully elucidated. In the present study, the effects of L-Asp on cell proliferation and apoptosis were investigated using the AML cell lines U937, HL-60 and KG-1a. The effects of combining L-Asp with mitoxantrone (MIT) and cytarabine (Ara-c) were also analyzed. The combination of MIT and Ara-C is known as MA therapy, and is a widely used therapeutic regimen for the treatment of elderly patients with refractory AML. When applied alone, L-Asp inhibited cell proliferation and induced apoptosis in each of the cell lines tested. Furthermore, the combined use of L-Asp with MA therapy further potentiated the inhibition of cell proliferation while increasing the induction of apoptosis. These findings provide evidence for the potential antitumor effect of L-Asp in AML, and indicate that improved efficacy maybe achieved by combining L-Asp with MIT and Ara-c. This combination may provide a promising new therapeutic strategy for the treatment of AML.

SUBMITTER: Chen T

PROVIDER: S-EPMC7401243 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Antiproliferative effects of L-asparaginase in acute myeloid leukemia.

Chen Tingting T Zhang Juan J Zeng Hui H Zhang Yue Y Zhang Yong Y Zhou Xiaohuan X Zhou Hebing H

Experimental and therapeutic medicine 20200618 3

The antitumor enzyme L-asparaginase (L-Asp) has commonly been used for the treatment of acute lymphoblastic leukemia. However, the effects of L-Asp on acute myeloid leukemia (AML) and their underlying mechanisms have not been fully elucidated. In the present study, the effects of L-Asp on cell proliferation and apoptosis were investigated using the AML cell lines U937, HL-60 and KG-1a. The effects of combining L-Asp with mitoxantrone (MIT) and cytarabine (Ara-c) were also analyzed. The combinati ...[more]

PMID: 32782519

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Project description:BackgroundGlucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI).ProcedurePatients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded.ResultsThe largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10-15 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4).ConclusionTriglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.

Dataset Information

Antiproliferative effects of L-asparaginase in acute myeloid leukemia.

Publications

Antiproliferative effects of L-asparaginase in acute myeloid leukemia.

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