title: Preclinical studies with triazinate (NSC-139105), an antifolate drug, in beagle dogs and rhesus monkeys.
abstract: The effects of the intravenous administration of triazinate by single and multiple injections were studied in beagle dogs and rhesus monkeys. In dogs, dose levels ranging from 0.3125 to 40 mg/kg were given either as single doses daily for 5 days, or once weekly for 6 weeks. The 5-day regimen was also studied in monkeys with dose levels from 2.5 to 40 mg/kg/day. Prominent drug-related and drug-dependent effects which appeared in both species were piloerection, muscular weakness, and respiratory difficulty which occurred during and immediately after the administration of dose levels of 10 mg/kg or greater. Gastrointestinal toxicity was severe in dogs but mild in monkeys. Lymphoid tissue toxicity was manifested by a circulating lymphopenia and localized cellular depletion in the germinal centers of lymphoid tissues. In dogs, signs of bone marrow toxicity consisted of a circulating neutropenia and, at necropsy, a reduction in the number of erythroid and myeloid elements plus megaloblastosis. Only the latter change was observed in monkeys. This difference in the hematopoietic toxicity between the beagle dog and the rhesus monkey was corroborated by the findings from in vitro studies with bone marrow. DNA synthesis in beagle bone marrow cells was depressed significantly by triazinate as compared with cells from rhesus marrow. A direct renal toxic effect was observed in monkeys given high doses of triazinate (20 and 40 mg/kg/day or 240-280 mg/m/day) for 5 days.
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells; D004247:DNA / Q000096:biosynthesis; D004064:Digestive System / Q000187:drug effects; D004285:Dogs; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000882:Haplorhini; D006410:Hematopoiesis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007928:Lethal Dose 50; D008231:Lymphopenia / Q000139:chemically induced; D008253:Macaca mulatta; D009132:Muscles / Q000187:drug effects; D009503:Neutropenia / Q000139:chemically induced; D010863:Piloerection / Q000187:drug effects; D012119:Respiration / Q000187:drug effects; D014227:Triazines / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D005493:Folic Acid Antagonists; D014227:Triazines; D004247:DNA; C012071:triazinate