talisomycin and Lung-Diseases

Rats were given daily subcutaneous injections of tallysomycin S10b (TLM) or bleomycin (BLM) for 6 days (1.25 or 2.50 mg/day). One half of each group was exposed to 80% oxygen for the last 4 days of drug treatment and then returned to room air. TLM produced marked mortality in contrast to equal doses of BLM. Exposure to 80% oxygen increased the lethality of either TLM and BLM treatments. The cause of death appeared to be related to pulmonary changes. Two weeks following the end of treatment in the low dose experiment, the lungs of surviving BLM-hyperoxia, TLM, and TLM-hyperoxia rats demonstrated severe vascular damage consistent with both endothelial cell and smooth muscle proliferation in pulmonary blood vessels. BLM-hyperoxia rats also demonstrated a more typical diffuse interstitial disease. All treatments produced an increase in lung-to-body weight ratio and a decrease in vital capacity and total lung compliance, as compared to age-matched controls. TLM toxicity was exacerbated by short-term exposure to 80% oxygen. Morbidity and mortality appeared to be related to severe lung changes similar to the hyperoxic potentiation of BLM lung disease.

Topics: Animals; Bleomycin; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Lung; Lung Diseases; Male; Oxygen; Rats; Rats, Inbred Strains; Respiratory Function Tests

Tallysomycin S10b, a biosynthetic derivative of tallysomycin B, was subjected to intravenous toxicologic studies in mice and dogs. LD50 and LD10 values from lethality studies in mice were utilized to establish dose levels for single and five daily dose toxicity studies in mice and dogs. Nephrotoxicity was the most consistent and prominent drug-related alteration in single and multiple dose studies in both species and was considered the dose limiting toxicity. Other toxicities included pulmonary toxicity, lymphopenia and necrosis of extremities in mice and dogs and testicular degeneration and focal vacuolation of adrenal cortical cells in the dog. Bleomycin was administered to dogs as a reference control agent at a single dose of 270 mg/m2 which was approximately equivalent to the highest tallysomycin S10b dose of 240 mg/m2. Tallysomycin S10b showed a greater nephrotoxic potential than bleomycin at earlier time periods. However, at termination there was no meaningful difference in the degree of chronic nephrotoxicity. The pulmonary toxicity of both drugs was comparable.

Topics: Animals; Bleomycin; Dogs; Female; Kidney Diseases; Lethal Dose 50; Lung Diseases; Male; Mice; Species Specificity