L-Asparaginase-Induced Pancreatic Injury is Associated with an Imbalance in Plasma Amino Acid Levels

Abstract

Background: The use of L-asparaginase (ASNase) to modify amino acid metabolism is one of the most effective chemotherapeutic means of inducing remission in acute lymphoblastic leukemia (ALL). However, severe pancreatitis sometimes occurs in patients receiving ASNase, because of an unknown mechanism. Objective: The purpose of the present study was to evaluate the relationship between ASNase-induced pancreatic injury and plasma amino acid levels in patients undergoing ASNase therapy. Methods: A total of 29 children aged 1-13.25 years (median age 4 years; male : female ratio 19 : 10) with ALL, who received induction therapy according to the Tokyo Children's Cancer Study Group L04-16 protocol, were studied. Levels of plasma amino acids and serum rapid turnover proteins (RTPs), pancreatic enzymes, and pancreatic protease inhibitors were measured before and 1, 2, 3, 4, 5, and 7 weeks after the first administration of ASNase. Results: Plasma asparagine levels were significantly lower after the first injection of ASNase (p < 0.01) and had almost recovered 2 weeks after the last ASNase injection. At 4 weeks after the first ASNase injection, serum aspartic acid, trypsin, and pancreatic secretory trypsin inhibitor (PSTI) levels remained significantly higher than those before the first ASNase injection (p < 0.01), and serum levels of prealbumin and transferrin remained significantly lower than those before the first ASNase injection (p < 0.01). Plasma amino acid and serum RTP levels gradually normalized after the last ASNase injection. Conclusions: Levels of serum trypsin and PSTI were elevated during the 2 weeks after administration of ASNase, which suggested the presence of subclinical pancreatitis. This period is similar to the time period in the present

Engineered asparaginase from Erwinia chrysanthemi enhances asparagine hydrolase activity and diminishes enzyme immunoreactivity ‐ a new promise to treat acute lymphoblastic leukemia

“…Despite being secondarily hydrolyzed by ASNase, Gln is the most abundant amino acid in the bloodstream; in the treatment of ALL, the serum concentration of Gln is drastically reduced during the administration of ASNase and, consequently, increased concentrations of Glu occur. 32,33 In combination with the product of Asn hydrolysis, Gln hydrolysis increases plasma ammonia levels up to sixfold higher than normal concentrations in pediatric and adult patients, which can lead to coma. 34,35 Gln is essential for several biological processes; the imbalance in the plasma concentrations of Gln and Glu causes high cellular stress and, consequently, the decrease/inhibition of protein synthesis in the body.…”

Strategies for targeting energy metabolism in Kirsten rat sarcoma viral oncogene homolog ‐mutant colorectal cancer

“…Research has identified that mutated KRAS regulates asparagine synthetase (ASNS), an enzyme that is involved in the de novo synthesis of asparagine from aspartate. KRAS‐mutant CRC cells can become adaptive to glutamine depletion through ASNS‐dependent asparagine biosynthesis and that the addition of exogenous asparagine can rescue the growth inhibition and cell death under glutamine‐free conditions . In addition to its role in glucose metabolism in cancer, recent studies have shown that KRAS‐mutant CRC cells may have adapted to glutamine consumption through ASNS‐dependent asparagine biosynthesis .…”

“…KRAS‐mutant CRC cells can become adaptive to glutamine depletion through ASNS‐dependent asparagine biosynthesis and that the addition of exogenous asparagine can rescue the growth inhibition and cell death under glutamine‐free conditions . In addition to its role in glucose metabolism in cancer, recent studies have shown that KRAS‐mutant CRC cells may have adapted to glutamine consumption through ASNS‐dependent asparagine biosynthesis . Moreover, the expression of ASNS was upregulated by the KRAS‐activated pathway, especially the PI3K‐AKT‐mTOR pathway .…”

“…52 In addition to its role in glucose metabolism in cancer, recent studies have shown that KRAS-mutant CRC cells may have adapted to glutamine consumption through ASNS-dependent asparagine biosynthesis. 52 Moreover, the expression of ASNS was upregulated by the KRASactivated pathway, especially the PI3K-AKT-mTOR pathway. 53 Furthermore, ASNS significantly inhibited tumor growth in KRAS-mutant CRC cells (HCT-116), and the combination of L-asparaginase (L-ASP) with rapamycin significantly inhibited tumor growth in vivo.…”

Cetoacidose diabética e pancreatite secundárias à peg-asparaginase.

“…Um aspecto importante quanto à pancreatite induzida por asparaginase é a ausência de hiperamilasemia na fase inicial em metade dos pacientes, como foi constatado no primeiro dia de internação. Esse fato é atribuído à deficiência da síntese proteica induzida pela asparaginase 14 . Dentro desse contexto amplo, a paciente foi conduzida de acordo com os protocolos de tratamento da pancreatite aguda, CAD e choque hipovolêmico grave adotados pelo serviço.…”