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

Abstract

BackgroundThe 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.ObjectiveThe 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.MethodsA 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.ResultsPlasma 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.ConclusionsLevels 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 study when the levels of plasma amino acids changed, thus suggesting that ASNase-induced pancreatic injury could be caused by the imbalance of plasma amino acid levels.

Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase

“…In the present study, ASNS inhibition significantly suppressed tumor growth in vivo of KRAS-mutant CRC cells (HCT116) ( Figure 4 A and Supplementary Figure S4 G ). Normal serum asparagine levels of mice and humans were reported to be 0.052 mM and 0.046 mM, respectively [22] , [45] . In sh ASNS transfectants, we found that the growth-inhibitory effects in vitro were recovered by exogenous addition of 0.1 mM asparagine ( Figure 3 , D–G and Supplementary Figure S5 A ).…”

“…In addition, the tumor cells within solid tumors in vivo are under a state of poorer nutrient, especially in the regions distant from tumor blood vessels. L-Asp treatment could diminish serum asparagine levels of mice and humans down to 0.004 and 0 mM, respectively [22] , [45] . ASNS induction by L-Asp treatment was reported to be the resistance mechanism of L-Asp in the treatment of ALL [46] .…”

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

“…In more than 50% of sporadic pancreatic ductal adenocarcinomas (PDAC), ASNS protein expression is very low (44), an observation that should be considered in light of the fact that normal exocrine pancreas has the highest basal ASNS expression of any tissue in the body (8,45). Moreover, pancreatitis is one of the primary clinical complications exhibited by ALL patients treated with ASNase (46), suggesting that pancreatic exocrine cells are particularly sensitive to Asn depletion. Consistent with low ASNS expression, PDAC cell lines were sensitive to ASNase, and the most sensitive expressed the lowest levels of ASNS (44).…”

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

“…KRAS-mutant CRC cells can become adaptive to glutamine depletion through ASNSdependent asparagine biosynthesis and that the addition of exogenous asparagine can rescue the growth inhibition and cell death under glutamine-free conditions. 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.…”

“…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.…”