Toxicologic and antitumor studies on 5-hydroxymethyldeoxyuridine.
Toxic effects of 5-hydroxymethyldeoxyuridine (HMUdR) were studied in white Swiss mice. Pathological, hematological, and clinical chemistry parameters were examined. Systemic toxicity was not observed in mice after ip administration of HMUdR in single doses up to 2000 mg/kg. Mice administered HMUdR daily for 15 days at 200 mg/kg, ip, manifested loss of weight, rough hair coat, diarrhea, swollen abdomens, weakness, lethargy, and a 20% mortality rate. Hematological and clinical chemistry parameters of all mice receiving HMUdR were within normal limits. At necropsy, all organs were grossly normal but microscopic examination of tissues of treated mice revealed the presence of shortened, thickened villi in the small intestine, nuclear vacuolation and necrosis of intestinal crypt epithelial cells, and some cytoplasmic vacuolation causing nuclear margination in hepatocytes. All histological lesions were reversible with cessation of treatment. HMUdR was active against murine L1210 and L5178Y leukemias in cell culture. The concentrations required to inhibit cell growth 50% compared to untreated cells was 2 and 4 microM, respectively. When HMUdR was administered ip at 50, 100, or 200 mg/kg in five daily doses to mice implanted with L1210 cells, life spans increased 20, 30, or 33% over placebo-treated controls.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy; D007940:Leukemia L5178 / Q000188:drug therapy; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D013936:Thymidine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; C018080:5-hydroxymethyl-2'-deoxyuridine; D013936:Thymidine