A comparison of the pulmonary toxicity produced by metal-free and copper-complexed analogs of bleomycin and phleomycin

Previous studies from this laboratory indicated that the terminal amine groups adjacent to the thiazole rings of bleomycins are important determinants of pulmonary toxicity. The present study examines the relation between pulmonary toxicity and molecular sites other than the terminal amine. Phleomycins differ from bleomycins in having a thiazoline instead of a thiazole ring. The contribution of the thiazole rings and also the metal binding sites were assessed by studying the pulmonary toxicity produced by metal-free and copper-complexed bleomycins and phleomycins bearing identical terminal amines. Bleomycin and phleomycin CHP; bleomycin B6, bleomycin B6 Cu, phleomycin G, phleomycin G Cu, bleomycin PEPP, bleomycin PEPP Cu, and phleomycin PEPP Cu (1 and 10 nmol) were administered to DBA 2J mice by the endotracheal route. The abilities of these analogs to produce pulmonary fibrosis and metaplasia were evaluated by histopathologic criteria and compared to the activity of a mixture of bleomycins (Blenoxane). Bleomycin B6 and phleomycin G tended to be more toxic than the other analogs, while the toxicities of bleomycin and phleomycin CHP and PEPP were comparable to Blenoxane. Analogous bleomycins and phleomycins with identical terminal amine groups were equally toxic. Copper-complexed analogs retained the toxicity of the respective metal-free bleomycin or phleomycin. These studies indicated that neither administration as a copperchelate nor substitution of a 4,5-dihydrothiazole ring for a thiazole ring affected pulmonary toxicity. These results are consistent with the importance of the variable bleomycin terminal amine groups in the production of lung injury.