TY - JOUR
T1 - Pancreatic tumor sensitivity to plasma L-asparagine starvation
AU - Dufour, Emmanuelle
AU - Gay, Fabien
AU - Aguera, Karine
AU - Scoazec, Jean Yves
AU - Horand, Françoise
AU - Lorenzi, Philip L.
AU - Godfrin, Yann
PY - 2012/8/1
Y1 - 2012/8/1
N2 - Objectives: 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.
AB - Objectives: 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.
KW - L-asparaginase
KW - L-asparagine synthetase
KW - cytotoxicity
KW - immunohistochemistry
KW - pancreatic carcinoma
KW - tissue micro array
UR - http://www.scopus.com/inward/record.url?scp=84863989495&partnerID=8YFLogxK
U2 - 10.1097/MPA.0b013e318247d903
DO - 10.1097/MPA.0b013e318247d903
M3 - Article
C2 - 22513289
AN - SCOPUS:84863989495
SN - 0885-3177
VL - 41
SP - 940
EP - 948
JO - Pancreas
JF - Pancreas
IS - 6
ER -