Arginine Depletion Slows Growth of Pancreatic Cancer

The majority of pancreatic cancer cells lack the ability to synthesize the amino acid arginine, and cancer researchers have shown that tumor growth can be significantly slowed if the cancer cells are prevented from obtaining arginine from outside sources.

Investigators at the University of California, Davis (Davis, CA, USA) assayed the expression of the enzyme argininosuccinate synthetase (ASS) in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic-cancer cell lines. In eukaryotic cells, ASS catalyzes the synthesis of arginine from aspartate and citrulline. However, ASS is poorly expressed in pancreatic cancer cells, and 87% of the tumors examined in this study lacked ASS expression, as did five of seven cell lines.

To prevent transplanted pancreatic tumors in a mouse model from obtaining exogenous arginine the mice were treated with a modified form of the enzyme arginine deiminase (ADI). ADI is a prokaryotic enzyme that metabolizes arginine to citrulline and found to inhibit melanoma and hepatoma cancer cells that expressed low levels of ASS. In this study, a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI) was used.

Results published in the October 15, 2008, issue of the International Journal of Cancer revealed that PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine, and tumor growth was inhibited by about 50%.

"Instead of killing cells as with typical chemotherapy, we instead removed one of the key building blocks that cancer cells need to function,” said senior author Dr. Richard Bold, professor of surgical oncology at the University of California, Davis. "We are looking at whether we can combine this treatment with certain kinds of chemotherapy. This additional research is needed to inform the clinical work and move it forward more quickly. The better we understand this process, the more we can use it in the fight against pancreatic cancer.”

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