Inhibition of Cell Cycle Progression of Human Pancreatic Carcinoma Cells in Vitro by l-(αS,5S)-α-Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic Acid, Acivicin (NSC 163501)

The inhibition of cell cycle progression of a human pancreatic carcinoma line, MiaPaCa-2, by l-(α S ,5 S )-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (Acivicin), an antimetabolite and glutamine antagonist, was investigated by means of flow cytometry, cell cycle kinetics, and cell enumeration. Flow cytometric criteria for logarithmically growing MiaPaCa-2 cells were established. Logarithmically growing cells exposed to 50 µm Acivicin appeared to markedly reduce their rate of cell cycle progression after they passed a point in later G1 phase or in early S phase. MiaPaCa-2 cells grew in the presence of 50 µm Acivicin with a population-doubling time of approximately 74 hr compared to a 20-hr doubling time for controls. The inhibition of cell cycle progression was at least partially reversed by removal of the drug. Based on previous reports of the biochemical mechanisms of Acivicin actions, several additives to the tissue culture medium were tested for their ability to protect MiaPaCa-2 cells from inhibition of cell cycle progression. Those cultures which contained cytidine partially protected the cells from Acivicin. The mechanism of inhibited growth induced by exposure to Acivicin is likely a complex reaction to the inhibition of several enzyme systems.