Preclinical toxicological evaluation of fostriecin, a novel anticancer antibiotic, in rats.
Fostriecin, a novel anticancer antibiotic produced by Streptomyces pulveraecus, 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, creatinine, 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.
Susick
R L
RL
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Hawkins
K L
KL
Pegg
D G
DG
D000475:Alkenes / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001772:Blood Cell Count; D004353:Drug Evaluation, Preclinical; D005260:Female; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011090:Polyenes; D011753:Pyrones; D051381:Rats; D011919:Rats, Inbred Strains
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D011090:Polyenes; D011753:Pyrones; C040313:fostriecin