Pancreatic tumor sensitivity to plasma L-asparagine starvation.

Abstract

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.

• Authors: Emmanuelle Dufour, Fabien Gay, Karine Aguera, Jean-Yves Scoazec, Françoise Horand, Philip L Lorenzi, Yann Godfrin
• Journal: Pancreas (Pancreas) Vol. 41 Issue 6 Pg. 940-8 (Aug 2012) ISSN: 1536-4828 [Electronic] United States
• PMID: 22513289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Asparagine
• Asparaginase
• Aspartate-Ammonia Ligase

Topics

• Animals
• Antineoplastic Agents (administration & dosage, blood)
• Asparaginase (administration & dosage, blood)
• Asparagine (blood, deficiency)
• Aspartate-Ammonia Ligase (metabolism)
• Blotting, Western
• Carcinoma, Pancreatic Ductal (blood, drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Down-Regulation
• Erythrocytes (enzymology)
• Humans
• Immunohistochemistry
• Injections, Intravenous
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Pancreatic Neoplasms (blood, drug therapy, enzymology, pathology)
• Time Factors
• Tumor Burden
• Xenograft Model Antitumor Assays