EFFECT OF 6-DIAZO-5-OXO-1-NORLEUCINE (DON) ON HUMAN CARCINOID-TUMOR CELL AGGREGATES

The induction of glutamine starvation has been suggested as a potentia l target for antitumoral treatment using inhibitors of amidotransferas e, an enzyme which mediates the conversion of glutamate to glutamine. Using multicellular aggregates from tumor cell lines, the effect of tr eatment with a suggested glutamine antagonist, 6-diazo-5-oxo-L-norleuc ine (DON), was investigated As indicators of treatment response, three different parameters were measured: aggregate size, uptake of C-14-me thionine and secretion of Chromogranin A. Of six cell types evaluated (carcinoid, glioma, neuroblastoma pancreas and bladder cancer), the la rgest inhibition of (14)Cmethionine uptake, amounting to 60 %, was fou nd in the carcinoid cell line BON. In this cell line the maximum effec t was reached already at 10 mu M concentration. DON induced marked gro wth inhibition in the BON aggregates which lasted 3 - 4 weeks after wh ich regrowth started. During this period the secretion of chromogranin and methionine uptake was also inhibited These studies suggest that t he neuroendocrine cell line BON is especially vulnerable to treatment by DON and show that strong inhibitory effects are found at concentrat ions lower than that achieved in patient blood in previous clinical tr ials.