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Biochemical and Pharmacological Effects of the Fermentation-derived Antitumor Agent, (S,5S)--Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic Acid (AT-125)¹

Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001 [G. L. N., A. E. B.], and Department of Experimental Therapeutics, J. T. Grace, Jr. Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263 [R. P. M., G. B. G., A. B.]

(S,5S)--Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125; -amino-3-chloro-2-isoxazoline-5-acetic acid; U-42126; NSC 163501) is a fermentation-derived amino acid antimetabolite 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. Further, especially in male mice, toxicity appears to be age related, younger animals being more sensitive. Similar effects have been observed previously with another antitumor agent, 3-deazauridine, suggesting common biochemical mechanisms of action. Coadministration of testosterone with AT-125 alleviates the toxicity of the agent and, in L1210 leukemic mice, allows administration of higher doses and a resulting enhanced therapeutic activity. Cytidine triphosphate synthetase, a glutamine-dependent amidotransferase and the primary locus of 3-deazauridine activity, was also shown to be inhibited strongly by AT-125 (K_i 2 x 10^–6 M). The effects of AT-125 on L1210 cell ribonucleotide pools (elevation of uridine triphosphate levels, decreases in cytidine triphosphate and guanosine triphosphate levels) were consistent with such inhibition and also suggested that inhibition of another glutamine-dependent enzyme, xanthosine 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 ribonucleosides (or deoxyribonucleosides) acted synergistically in reversing the growth-inhibitory activity of AT-125 towards L1210 cells in culture.

¹ This study was supported in part by Contract N01-CM-43753 with the Division of Cancer Treatment and by Grants CA-12585 and CA-17156 from the National Cancer Institute, USPHS.

² Affiliated with Cancer Research, The Upjohn Company, Kalamazoo, Mich. 49001.

Received 10/13/78. Accepted 12/ 5/78.

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