L-carnitine does not ameliorate asparaginase-associated hepatotoxicity in a C57BL6 mouse model

Liu, Yiwei; Janke, Laura J.; Li, Lie; Relling, Mary V.

doi:10.1080/10428194.2019.1571198

Cited by 8 publications

(9 citation statements)

References 15 publications

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“…High-fat diets routinely induce hepatosteatosis in mice, which was observed in all groups in our study. Lack of hepatotoxicity in our model may have been due to confounding effects of the weight loss caused by PEG-ASNase, or secondary to the relatively low dose used in our study, compared to other animal studies in which PEG-ASNase induced notable toxicity [20,42]. However, others have found that lower doses of native ASNase decreased serum asparagine to undetectable levels [43,44].…”

Section: Discussionmentioning

confidence: 69%

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

Sea

Orgel

Chen

et al. 2019

Leukemia & Lymphoma

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Asparaginase (ASNase) is an integral part of pediatric induction chemotherapy that has also been shown to improve adult survival rates; however, pegylated (PEG)-ASNase induces severe hepatotoxicity in this population. Recent case reports describe the incorporation of levocarnitine (LC) supplementation into PEG-ASNase-containing induction regimens to prevent or treat hepatotoxicity. Because LC facilitates the metabolism of free fatty acids (FFA), a primary fuel source for ALL cells, LC could potentially interfere with ALL chemotherapy efficacy. To test this, we employed in vitro and in vivo models of ALL. We show in vitro that LC supplementation does not impact cytotoxicity from vincristine, daunorubicin, dexamethasone, or ASNase on human ALL cells nor lead to an increase in ALL cell metabolic rate. In vivo, we demonstrate LC does not impair PEG-ASNase monotherapy in mice with syngeneic ALL. Together, our findings show that LC supplementation is a safe strategy to prevent/reverse ASNase-induced toxicities in preclinical models.

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Section: Discussionmentioning

confidence: 69%

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

Sea

Orgel

Chen

et al. 2019

Leukemia & Lymphoma

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“…The onset of liver injury correlates with the development of hepatic steatosis, including in a study of 31 pediatric patients which detected the presence of hepatic steatosis among 87% of patients receiving ASNase, indicating that the agent may induce fatty liver rather than liver injury being a pre-existing condition 17 . Concordant with clinical studies demonstrating that ASNase induces fatty liver, several preclinical investigations have also indicated that mice develop fatty liver after ASNase 18 , 19 , 20 , 21 , 22 , 23 .…”

Section: Introductionmentioning

confidence: 56%

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Kumar

Hoshitsuki

Rathod

et al. 2021

Acta Pharmaceutica Sinica B

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PEGylated- l -asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β -oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara , Lcad/Mcad , Hadhb , Apob100 , and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

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“…Levocarnitine supplementation was defined as “prophylaxis” when started anytime prior to PEG‐ASP exposure. 28 As the rationale for starting supplementation after PEG‐ASP was not generally known (and was potentially due to early evidence or concerns for hepatotoxicity), levocarnitine started anytime following the first dose of PEG‐ASP was classified as “rescue.” AYA age was classified as 15–39 years old at diagnosis. 29…”

Section: Methodsmentioning

confidence: 99%

Levocarnitine for pegaspargase‐induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia

et al. 2021

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L-carnitine does not ameliorate asparaginase-associated hepatotoxicity in a C57BL6 mouse model

Cited by 8 publications

References 15 publications

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Levocarnitine for pegaspargase‐induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia

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