Biochemicaland PharmacologicalEffectsof the Fermentation-derived AntitumorAgent, (aS,5S)-a-Amino-3-chloro-4,5-di hydro-5- isoxazoleaceticAcid(AT-i25)1

(aS,5S)-a-Amino-3-chloro-4,5-d ihydro-5-isoxazoleacetic acid (AT-i 25; a-amino-3-chhono-2-isoxazohine-5-aceticacid; U-42126;NSC 163501)is a fermentation-derived amino acid antimetabohite with significant antitumor activity. It has been shown previously to act in mammalian cells as a glutamine antagonist. In the present studies, AT-125 has been shown to exhibit sex-related toxicity towards mice; females are considerably more sensitive than males. Fur them,especially in male mice, toxicity appears to be age related, younger animals being more sensitive. Similar effects have been observed previously with another antitu momagent, 3-deazauridine, suggesting common biochemi cal mechanisms of action. Coadministration of testosterone with AT-125alleviates the toxicity of the agent and, in Li 210 leukemic mice, allows administration of higher doses and a resulting enhanced therapeutic activity. Cytidine triphos phate synthetase, a glutamine-dependent amidotransferase and the primary locus of 3-deazaunidine activity, was also shown to be inhibited strongly by AT-125 (K 2 x i0@ M). The effects of AT-i25 on Li210 cell ribonucheotide pools (elevation of uridine tniphosphate levels, decreases in cyti dine tniphosphate and guanosine tniphosphate levels) were consistent with such inhibition and also suggested that inhibition of another glutamine-dependent enzyme, xantho sine monophosphate aminase, might be important in the action of this agent. Further support for such a hypothesis was provided when it was observed that a combination of cytosine and guanosine nibonucleosides (or deoxymibonu cleosides) acted synergistically in reversing the growth inhibitory activity of AT-l25 towards Li2lO cells in culture.