title: Pancreatic tumor sensitivity to plasma L-asparagine starvation.
abstract: OBJECTIVE
  In this study, our aim was to test whether asparagine synthetase (ASNS) deficiency in pancreatic malignant cells can lead to sensitivity to asparagine starvation. We also investigated, in tumor-bearing mice, the efficacy of L-asparaginase entrapped in red blood cells (RBCs), a safe formulation, to induce asparagine depletion.
  
  
  METHODS
  First, ASNS expression was evaluated by immunohistochemistry in sporadic pancreatic ductal adenocarcinoma. Then, 4 pancreatic carcinoma cell lines were examined by Western blot, immunocytochemistry, and cytotoxicity assay to L-asparaginase and in asparagine-free or reduced-asparagine media. Finally, mice bearing the most in vitro sensitive cell line received RBC-entrapped L-asparaginase to investigate the anticancer efficacy of serum asparagine depletion in vivo.
  
  
  RESULTS
  Approximately 52% of pancreatic adenocarcinomas expressed no or low ASNS. The highest in vitro cytotoxicity to L-asparaginase or to reduced asparagine medium was observed with SW1990 line when ASNS expression was the lowest. In vivo sensitivity was confirmed for this cell line.
  
  
  CONCLUSIONS
  Plasma asparagine depletion by RBC-entrapped L-asparaginase in selected patients having no low or no ASNS may be a promising therapeutic approach for pancreatic cancer.
authors.affiliation: Research and Development Department, ERYTECH Pharma, Lyon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Dufour
authors.forename: Fabien
authors.initials: F
authors.lastname: Gay
authors.forename: Karine
authors.initials: K
authors.lastname: Aguera
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Françoise
authors.initials: F
authors.lastname: Horand
authors.forename: Philip L
authors.initials: PL
authors.lastname: Lorenzi
authors.forename: Yann
authors.initials: Y
authors.lastname: Godfrin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood; D001215:Asparaginase / Q000008:administration & dosage* / Q000097:blood; D001216:Asparagine / Q000097:blood / Q000172:deficiency*; D001217:Aspartate-Ammonia Ligase / Q000378:metabolism*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D004912:Erythrocytes / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001216:Asparagine; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase