Mechanism of sensitivity of cultured pancreatic carcinoma to asparaginase

The effects of E. coli L‐asparaginase on cultured human pancreatic carcinoma (MIA PaCa‐2) have been studied. The enzyme (1 U/ml) inhibited growth and protein synthesis in both MIA PaCa‐2 and PANC‐1, another pancreatic carcinoma cell line, but had little or no effect on human breast carcinoma or melanoma cells. The inhibition of protein synthesis by E. coli L‐asparaginase was largely reversed by L‐glutamine but not by L‐asparagine. The growth of both MIA PaCa‐2 and PANC‐1 showed absolute dependence on L‐glutamine. These results indicate that the effect of E. coli L‐asparaginase on cultured pancreatic carcinoma cells is exerted at least in part through its L‐glutaminase activity. Although the addition of L‐glutamine to the culture appeared to prevent cell death caused by L‐asparaginase, it did not restore the ability of the cells to proliferate. Asparaginase derived from vibrio succinogenes, which is virtually free of L‐glutaminase activity, was equally inhibitory to MIA PaCa‐2 cell growth but did not affect protein synthesis. It is concluded that the inhibition of growth of cultured pancreatic carcinoma cells by E. coli asparaginase is a combined function of both its L‐asparaginase and L‐glutaminase activity.