ACIVICIN - AN ANTI-TUMOR ANTIBIOTIC

  • 1 January 1981
    • journal article
    • research article
    • Vol. 4  (3) , 327-330
Abstract
Acivicin [(.alpha.S,5S)-.alpha.-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; AT-125; NSC-163501] is a fermentation product of Streptomyces sviceus which is active in a variety of mouse tumor models including the L1210 and P388 leukemias, the M5076 ovarian carcinoma and the MX-1 human breast tumor xenograft. Antitumor activity is probably mediated through the inhibition of enzymes catalyzing amido transfer from L-glutamine, especially CTP synthetase and XMP aminase. In mice, acivicin is absorbed systemically via the per os, i.p., and s.c. routes and is predominantly excreted in the urine in unchanged form. Although a wide variety of toxicities, including myelosuppression, were noted in dogs and monkeys, vomiting, diarrhea and pathologic lesions of the GI [gastrointestinal] tract predominated in both species. A marked cumulative toxicity was noted in dogs with 16 mg/m2 per day being the LD on the 5-times-daily schedule compared to 1000 mg/m2 on the single-dose schedule. An interesting phenomenon was noted in mice; older male mice were more resistant to the toxic effects of the drug than female or younger male mice. This sex and age difference in susceptibility to acivicin toxicity was correlated with differences in pharmacokinetics; older male mice cleared acivicin at approximately twice the rate of females or younger males. No sex differences in toxicity were noted in dogs or monkeys. Because of its activity in mouse tumor systems and acceptable preclinical toxicology patterns, the drug is being introduced into clinical phase I studies under the sponsorship of the National Cancer Institute, [USA].