Effect of l-glutamine antagonists on 5-phosphoribosyl 1-pyrophosphate levels in p388 leukemia and in murine colon adenocarcinomas in vivo

Abstract

The intratumoral content of 5-phosphoribosyl 1-pyrophosphate (PRPP) and the acitivity of the enzymes anabolizing and catabolizing the sugar phosphate were determined following i.p. administration of an ld 10 dose of an l-glutamine antagonist or saline to tumor-bearing animals. Elevation of PRPP pool size following administration of l-[αS,5S]-α-amino-3-chloro-4,5-dihydro-5-isopazoleacetic acid (NSC-163501) (AT-125) was maximal at 8 hr and returned to pretreatment levels by 24 hr. In P388 leukemia, dose for dose, at 4 hr, 6-diazo-5-oxo- l-norleucine (NSC-7365) (DON) was the most potent of the l-glutamine antagonists in elevating basal PRPP pool size (507% above control) followed by AT-125 and azaserine, 300 and 100% above control respectively. Moreover, such augmentation in PRPP pool size preferentially affected P388 tumor rather than the small intestine. Following i.p. administration of ld 10 doses of AT-125, DON and azaserine, the specific activities of PRPP anabolizing and catabolizing enzymes were determined. A significant inhibition of PRPP amidotransferase was demonstrated with DON and AT-125 (P < 0.05), and no inhibition with azaserine. A similar modulation of PRPP pool size was demonstrated in vivo following administration of 250 mg/kg of AT-125 in mice bearing colonic adenocarcinoma lines. It was suggested that a significant increase of PRPP pool size might cause the possible synergism of a selected l-glutamine antagonist and 5-fluorouracil as reported after the appropriately scheduled administration of methotrexate and 5-fluorouracil.