LSC 2014 abstract - Deglycosylated bleomycin, while keeping bleomycin's antitumor activity, is devoid of its strong pulmonary toxicity

Abstract

Introduction: The therapeutic efficacy of the chemo-agent bleomycin (BLM) is restrained because of its lung toxicity with pulmonary fibrosis (PF) being the most devastating form. The deglycosylated form of BLM (DBLM) is obtained by chemical synthesis. DBLM and BLM are both able to induce tumoral cell apoptosis in vitro. We assessed DBLM anticancerous activity and lung toxicity in vivo.

Methods: BLM and DBLM were administred intraperitoneally in two rodent models of tumor (human lymphoma xenograft & syngeneic melanoma models). Lung toxicity was assessed in vivo by intra-tracheal administration of BLM, DBLM or NaCl in C57BL/6 mice and in vitro on epithelial A549 cells.

Results: We demonstrate in vivo in both cancer models that DBLM inhibited tumour growth (p<0.05 in tumor size compared to NaCl) similarly to BLM but without a loss in mouse body weight (p<0.01 // BLM group). When administered intratrachealy to C57BL/6 mice, DBLM did not induced collagen accumulation (p<0.01 // BLM group) and PF (Masson Trichrome) compared to BLM-injected mice lung. DBLM, as BLM, induced lung epithelial cell death in vivo (TUNEL) but failed to induce 1) inflammation in the BAL (cell count, MCP, IL6), 2) ROS production and 3) TGF-β1 overproduction (ELISA) as observed in the BLM group.

In vitro BLM induce massive cell death in epithelial cells compared to DBLM treatment. This effect is accompanied with caspase-1 activation in A549.

Conclusion: This study highlights the antitumorigenic properties of DBLM, the modified form of BLM. DBLM does not induce PF in rodent. We propose that DBLM should be considered a clinical less-toxic alternative to BLM in cancer therapy.