Mechanisms of bleomycin-induced lung damage

Bleomycins are a family of compounds produced by Streptomyces verticillis. They have potent tumour killing properties which have given them an important place in cancer chemotherapy. They cause little marrow suppression, but pulmonary toxicity is a major adverse effect. The mechanisms of cell toxicity are well described based on in vitro experiments on DNA. The bleomycin molecule has two main structural components: a bithiazole component which partially intercalates into the DNA helix, parting the strands, as well as pyrimidine and imidazole structures, which bind iron and oxygen forming an activated complex capable of releasing damaging oxidants in close proximity to the polynucleotide chains of DNA. This may lead to chain scission or structural modifications leading to release of free bases or their propenal derivatives. The mechanisms are well described based on in vitro experiments on DNA, but how they relate to intact cells in whole animals is more tenuous. Bleomycin is able to cause cell damage independent from its effect on DNA by induction lipid peroxidation. This may be particularly important in the lung and in part account for its ability to cause alveolar cell damage and subsequent pulmonary inflammation. The lung injury seen following bleomycin comprises an interstitial oedema with an influx of inflammatory and immune cells. This may lead to the development of pulmonary fibrosis, characterized by enhanced production and deposition of collagen and other matrix components. Several polypeptide mediators capable of stimulating fibroblasts replication or excessive collagen deposition have been implicated in this, but the precise role of these in bleomycin-induced fibrosis is yet to be demonstrated. Current therapy for bleomycin-induced lung damage is inadequate, with corticosteroids most often used. Given the mechanism of action described above, antioxidants and iron chelators might be beneficial. Although, studies to date are equivocal and there is insufficient evidence to promote their use clinically. Novel drugs are currently being developed and it is hoped these may be more useful.