© 1990 Oxford University Press
research-article |
Preclinical Toxicological Evaluation of Fostriecin, a Novel Anticancer Antibiotic, in Rats
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105
Received November 27, 1989; accepted April 17, 1990
Preclinical Toxicological Evaluation of Fostriecin, a Novel Anticancer Antibiotic, in Rats. SUSICK, R. L., JR., HAWKINS, K. L., AND PEGG, D. G. (1990). Fundam Appl. Toxicol. 15,258–269. Fostriecin, a novel anticancer antibiotic produced by Steptomycespulveraecus, is believed to act via inhibition of topoisomerase II. Single-dose intravenous administration to rats at dose levels of 8.8 to 48 mg/kg resulted in lethality at dose levels of 35 mg/kg and higher. Major toxic effects were observed primarily at 17.5 mg/kg and higher, were reversible, and consisted of bone marrow hypocellularity, leukopenia, neutropenia, thrombocytopenia, and diffuse necrosis of various lymphoid tissues. The kidney was also identified as a target organ. Renal effects were observed primarily at 20 mg/kg, were reversible, and included increases in serum BUN, creati-nine, and 24-hr glucose excretion. Twenty-four-hour excretion of Na+, K+ and urine osmolality were decreased postdosing at 10 and 20 mg/kg. Renal lesions, observed primarily at 20 mg/kg, consisted of vacuolization and necrosis of proximal and distal tubular epithelium at the corticomedullary junction extending into the medulla. Repeated daily intravenous administration of fostriecin for 5 days to rats at dose levels of 2.5 to 26.5 mg/kg resulted in death at 10 mg/ kg and above and similar hematologic, bone marrow, lymphoid tissue, and renal changes as observed in the single-dose study. Hematological, bone marrow, lymphoid, and renal changes observed in rats were consistent with the cytotoxic mechanism of action of the compound