Bleomycin pulmonary toxicity: production of fibrosis by bithiazole-terminal amine and terminal amine moieties of bleomycin A2.

We have previously demonstrated that endotracheal administration of the terminal amines of several bleomycins, when administered as the free amines, produce pulmonary fibrosis of severity comparable to the intact drug. In the present report, bleomycin A2 and its sulfonium ion-containing terminal substituents, with and without the bithiazole rings, were administered to mice endotracheally. The incidence and severity of epithelial metaplasia was greater with the intact drug in comparison to the terminal substituents. In contrast, the terminal substituents and intact drug produced similar degrees of fibrosis. These results underscore the importance of the variable bleomycin terminal substituents in the pathogenesis of pulmonary fibrosis.