Subchronic Intravenous Toxicity of the Antineoplastic Drug, Amsacrine, in Male Wistar Rats

Amsacrine, a DNA intercalator and topoisomerase II inhibitor,is efficacious as an antileukemogenic agent. This study wasconducted to assess the subchronic toxicity of amsacrine inrats following a cyclic clinical dosing regimen and as a range–findingexperiment for a subsequent carcinogenicity bioassay. Groupsof 30 male Wistar rats were administered drug intravenouslyat doses of 0, 0.25, 1.0, and 3.0 mg/kg daily for 5 days followedby 23 days without treatment. This cycle of dosing and recoverywas repeated six times to simulate human clinical usage of thedrug. Assessments of hematology, clinical chemistry, and grossand microscopic pathology were conducted 3 and 21 days followingcompletion of dosing in the first, third, and sixth cycles.There were no deaths during the study. Hair loss, diarrhea,tail injuries, chromodacryorrhea, and rhinorrhea were observedprimarily in animals administered 3 mg/kg. Hair loss and diarrheaoccurred during periods of dosing and generally resolved duringthe recovery phase of each cycle. Both of these signs becameprogressively more severe during the latter half of the study.Body weight loss and reduced food consumption also occurredin the 3 mg/kg group during each week of dosing. At study termination,mean body weight and food consumption of the 3 mg/kg group weresignificantly less than those of controls by approximately 20and 50%, respectively. Marked, reversible leukopenia associatedwith reductions in both neutrophil and lymphocyte counts occurredin cycles one and three in animals administered 1 and 3 mg/kg,respectively. Reversible neutropenia was also observed in the3 mg/kg group in cycle 6. Similar effects on platelet countswere seen in the 3 mg/kg group in all three cycles analyzed.Absolute and relative testes weights of the 3 mg/kg group weresignificantly less than the vehicle controls at all time pointsin the third and sixth cycles. Relative testes weights werealso decreased in the 1 mg/kg group in cycle 6.