title: Chronic toxicity of the anticancer agent trimetrexate in rats.
abstract: Trimetrexate was administered to rats in an interrupted treatment regimen comparable to proposed human clinical treatment. Forty-five rats of each sex were dosed intravenously with trimetrexate at 0, 1, 10, or 30 mg/kg (0, 6, 60, or 180 mg/m2), once daily for 5 consecutive days, followed by a 23-day recovery period. This cycle of dosing and recovery was repeated for a total of six cycles. Hematology, urinalysis, clinical chemistry, and gross and microscopic pathology examinations were conducted for animals euthanatized 3 and 21 days after dosing cycles 1, 3, and 6. Additional rats in each group were maintained without dosing for an additional 56 days (77 days after the last trimetrexate dose) to assess the long-term reversibility of pathologic changes. Target organs were typical for an antifolate and included gastrointestinal tract, lymphoid tissues, and the hematopoietic and male reproductive systems. No toxicity was observed at 1 mg/kg. Treatment-related changes in hematology parameters following 10 and 30 mg/kg were fully reversible within 3 weeks of each dosing cycle. Except for testis and cecum, histopathological changes were also reversible within 21 days of dosing. Trimetrexate-induced testicular changes persisting during the course of multiple cycles of dosing were not reversible within 21 days, but required an additional 56 days for essentially complete recovery.
authors.affiliation: Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105-2430.
authors.forename: L A
authors.initials: LA
authors.lastname: Dethloff
authors.forename: J R
authors.initials: JR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D004906:Erythrocyte Count / Q000187:drug effects; D005260:Female; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D016597:Trimetrexate / Q000633:toxicity*
chemical_list: D012709:Serum Albumin; D016597:Trimetrexate