title: Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity.
abstract: Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy.
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Burgy
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Wettstein
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France.
authors.forename: Pierre S
authors.initials: PS
authors.lastname: Bellaye
authors.affiliation: Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon 21079, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Decologne
authors.affiliation: Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon 21079, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Racoeur
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Goirand
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalier Universitaire (CHU), Dijon 21079, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Beltramo
authors.affiliation: Institut des Biomolécules Max Mousseron, Faculty of Pharmacy, University of Montpellier, Montpellier 34093, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hernandez
authors.affiliation: Department of Biochemistry, University of Monastir, Monastir 5000, Tunisia.
authors.forename: Abderraouf
authors.initials: A
authors.lastname: Kenani
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalier Universitaire (CHU), Dijon 21079, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Camus
authors.affiliation: Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon 21079, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. Anticancer Centre Georges François Leclerc, CGFL, Dijon 21079, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: INSERM, LNC UMR 866, Laboratoire d'Excellence LipSTIC, Dijon 21079, France. Equipe "Heat Shock Proteins" Labellisée par la Ligue Nationale contre le Cancer, Dijon 21079, France. Faculty of Medicine and Pharmacy of Dijon, Université Bourgogne Franche-Comté, Dijon 21079, France. Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalier Universitaire (CHU), Dijon 21079, France. philippe.bonniaud@chu-dijon.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonniaud
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000150:complications / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D017382:Reactive Oxygen Species; D001761:Bleomycin; C033284:deglycobleomycin; D020170:Caspase 1