Effect of L-glutamine antagonists on 5-phosphoribosyl 1-pyrophosphate levels in P388 leukemia and in murine colon adenocarcinomas in vivo.
The intratumoral content of 5-phosphoribosyl 1-pyrophosphate (PRPP) and the activity of the enzymes anabolizing and catabolizing the sugar phosphate were determined following i.p. administration of an LD10 dose of an L-glutamine antagonist or saline to tumor-bearing animals. Elevation of PRPP pool size following administration of L-[alpha S,5S]-alpha-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 (50% 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 LD10 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 less than 0.05), and no inhibition with azaserine. A similar modulation of PRPP pool size demonstrated in vivo following administration of 250 mg/kg of ART-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.
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D001377:Azaserine / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism*; D003980:Diazooxonorleucine / Q000494:pharmacology; D005973:Glutamine / Q000037:antagonists & inhibitors*; D007421:Intestine, Small / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007941:Leukemia P388 / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism; D010428:Pentosephosphates / Q000378:metabolism*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism*
D007555:Isoxazoles; D010428:Pentosephosphates; D003980:Diazooxonorleucine; D005973:Glutamine; D010754:Phosphoribosyl Pyrophosphate; D001377:Azaserine; C006303:acivicin