P105 Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity

Bleomycin is an anti-cancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors. Unfortunately, bleomycin has major, pulmonary toxicity that affects 20% of treated individuals with pulmonary fibrosis being the most devastating form. Deglyco-bleomycin is a molecule derived from bleomycin in which the sugar residue D-mannosyl-L-glucose disaccharide has been deleted. The objective of this study is to assess the anti-cancerous activity and the lung toxicity of deglyco-bleomycin. We compared in vivo the antitumor activity in three rodent models after intraperitoneal administrated deglyco-bleomycin and bleomycin. Pulmonary toxicity was in depth examined after intratracheal administration of both chemotherapeutic agents. We demonstrate in vivo in rodent cancer models, including a human Hodgkin lymphoma xenograft and a syngeneic melanoma model, that intra-peritoneal deglyco-bleomycin is as effective as bleomycin in inducing tumor regression. However, while this bleomycin-induced anti-tumor effect was accompanied by a loss in body weight and the development of pulmonary toxicity, deglyco-bleomycin did not affect body weight and did not engender lung injury. Whereas both molecules were able to induce lung epithelial cells apoptosis after intra-tracheal administration, deglyco-bleomycin lost the ability to induce the production of ROS, caspase-1 activation, TGF-beta1 and other pro-fibrotic and inflammatory cytokines in mouse lung. Deglyco-bleomycin should be considered for clinical testing as a non-toxic alternative to bleomycin in cancer therapy.